WO2021063335A1 - Erk1/2 protein kinase inhibitor and use thereof - Google Patents

Abstract

The present application provides a compound represented by formula (I), or isomer or pharmaceutically acceptable salt thereof, and use thereof in the preparation of an ERK1/2-mediated disease drug.

Description

ERK1/2 protein kinase inhibitor and its use Technical field

This application belongs to the field of chemistry and medicine, and specifically relates to an ERK1/2 protein kinase inhibitor and its use.

Background technique

Extracellular signal-regulated kinase (ERK1/2) is a widely expressed protein serine/threonine kinase and one of the important subfamily of the mitogen-activated protein kinase (MAPK) family. The MAPK pathway is an evolutionary conserved cell signaling pathway that regulates various cellular processes, including cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation, and transcription. The ERK/MAPK signaling pathway responds to extracellular stimulation of the cell surface receptor tyrosine kinase (RTK). When RTK is activated, RAS GTPases (K-RAS, N-RAS, and H-RAS) convert from an unactivated GDP-bound state to an activated GTP-bound state. Activated RAS activates the kinase activity of RAF (A-RAF, B-RAF and C-RAF) by phosphorylating the downstream RAF effector protein, which in turn phosphorylates and activates the dual-specific kinase MEK (MEK1/2). Then, the activated MEK phosphorylates and activates ERK1/2. Phosphorylation activated ERK1/2 is translocated from the cytoplasm to the nucleus, and then mediates the transcriptional activation of Elk-1, ATF, NF-κB, Ap-1, c-fos and c-Jun, and participates in a variety of biological reactions , Including cell proliferation and differentiation, cell morphology maintenance, cytoskeleton construction, cell apoptosis and cell malignancy, etc.

ERK and its signal pathway play a role in mediating and amplifying signals in the process of tumor invasion and metastasis. In many human cancers, abnormal activation of multiple protein mutations in the ERK signal pathway can be found, which ultimately leads to the excessive activation of ERK kinase activity. . Approximately 30% of human cancers contain activating RAS mutations (Roberts and Der, Oncogene. 2007; 26: 3291-3310). KRAS is the most common mutant subtype, mutated in 22% of tumors. KRAS mutations are especially common in pancreatic cancer (70-90%), non-small cell lung cancer (10-20%), and colorectal cancer (25-35%) (Neuzilletetal., 2014. Pharmacol. Ther. 141; 160-171) ). N-RAS mutations and H-RAS mutations occur in 8% and 3% of cancers, respectively (Prior et al., Cancer Res. 2012; 72(10); 2457-2467). It is worth noting that it is reported that 15-20% of melanoma cases have activated N-RAS mutations. In addition, 8% of all tumors have B-RAF mutations. The majority of B-RAF mutations are B-RAF ^V600E mutations. This mutation is found in melanoma (50-60%) and papillary thyroid cancer (40-60%). %), colorectal cancer (5-10%) and non-small cell lung cancer (3-5%) are especially prevalent (Neuzillet et al., 2014. Pharmacol. Ther. 141; 160-171), which makes B- RAF can be continuously activated without RAS phosphorylation activation. At present, a number of anti-tumor drugs that specifically target the B-RAF ^V600E mutation have been marketed, and have shown good curative effects in diseases such as melanoma. However, so far there is no specific targeted drug on the market for ERK, the key kinase at the most downstream of the entire MAPK signaling pathway. On the other hand, all ^{drugs targeting B-RAF V600E} mutations currently on the market have developed severe drug resistance within less than a year of treatment. A large number of clinical studies have shown that, in addition to common drug resistance mutations, abnormal reactivation of ERK kinase activity is an important mechanism for drug resistance. Therefore, the development of new specific ERK inhibitors can be used as a new type of anti-tumor drug, and at the same time, it can be used as a ^{second-line drug after a variety of B-RAF V600E} mutation inhibitor drugs are resistant. It is very important in anti-tumor therapy. Clinical and market value.

ERK1/2 inhibitors with rapid clinical progress, such as Ulixertinib (Phase II), ASTX-029, etc., have shown good biological activity. However, Ulixertinib's defects in drug metabolism have resulted in higher clinical doses and more frequent administration methods, which have imposed greater restrictions on its further clinical development. And ASTX-029 also has a strong inhibitory activity on the proliferation of B-RAF wild-type tumor cells, which in turn may show strong clinical toxicity.

Summary of the invention

This application discloses a class of compounds that can be used as ERK1/2 protein kinase inhibitors and their use in preparing drugs for ERK2-mediated diseases.

In one aspect, this application provides a compound of formula (I):

Or its isomer or pharmaceutically acceptable salt;

Wherein, X and Y are independently selected from C or N;

R ^{1 is} selected from C _1-6 alkyl, 3- to 9-membered cycloalkyl, 3- to 9-membered heterocycloalkyl containing 1-3 N or O, aryl or containing 1-3 N or O Wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted with one or more R ⁶ , wherein R ^{6 is} selected from C _{1 -6} alkyl, halogen, hydroxy, carbonyl, amino, cyano, alkoxy, -(CH ₂ ) _n COOH or -(CO)(CH ₂ ) _n CH ₃ ;

R ^{2 is} selected from hydrogen, halogen, alkoxy or C _1-6 alkyl optionally substituted with one or more fluorine atoms;

R ^{3 is} selected from ^{an aryl group optionally substituted with 0-3 R 7} or a 5- to 6-membered heteroaryl group, wherein R ^{7 is} selected from halogen, alkoxy or optionally substituted with one or more fluorine atoms C _1-6 alkyl;

R ^{4 is} selected from -(CH ₂ ) _n OH or -COOH;

R ^{5 is} selected from C _1-6 alkyl; and

Each n is independently an integer between 0-3.

In some embodiments, formula (I) is formula (Ia):

Wherein: R ^{2 is} _{selected from hydrogen, halogen or C 1-6} alkyl optionally substituted with one or more fluorine atoms; R ^{3 is} selected from ^{aryl optionally substituted with 0-3 R 7} , wherein R ^{7 is} _{selected from halogen, alkoxy or C 1-6} alkyl optionally substituted with one or more fluorine atoms; R ⁴ is -(CH ₂ ) _n OH; and each n is independently 0-3 Integer between.

In other embodiments, formula (I) is formula (Ib):

Wherein R ^{2 is} selected from hydrogen, chlorine or trifluoromethyl; R ^{7 is} selected from halogen, methyl, methoxy or trifluoromethyl; and R ¹ , X and Y have the meanings defined above.

In other embodiments, formula (Ib) is formula (Ib-1):

Wherein R ¹ , R ² and R ⁷ have the meanings defined above.

In other embodiments, formula (Ib) is formula (Ib-2):

Wherein R ¹ , R ² and R ⁷ have the meanings defined above.

In other embodiments, formula (Ib) is formula (Ib-3):

Wherein R ¹ , R ² and R ⁷ have the meanings defined above.

In other embodiments, formula (Ib) is formula (Ib-4):

Wherein R ¹ , R ² and R ⁷ have the meanings defined above.

The aforementioned heterocycloalkyl groups are monocyclic or polycyclic (including 2 or more fused rings, including spiro, fused or bridged systems, such as bicyclic ring systems), saturated or unsaturated non-aromatic 4 A to 15-membered ring system, including 1 to 14 ring-forming carbon atoms and 1 to 10 ring-forming heteroatoms, the ring-forming heteroatoms are independently selected from O, S, N, P, and B. The heterocycloalkyl group may also optionally contain one or more oxo (ie, =O) or thiocarbonyl (ie, =S) groups. For example, a 4 to 12 membered heterocycloalkyl is a monocyclic or polycyclic, saturated or unsaturated, non-aromatic 4 to 12 membered ring system that contains one or more ring-forming heteroatoms.

The aforementioned aryl group is an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. The aryl group can have 6 to 10 carbon atoms in one or more rings. Most commonly, aryl groups have 6 carbon atoms in the ring. For example, a C6-10 aryl group is an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.

The aforementioned heteroaryl group is a monocyclic or fused-ring polycyclic aromatic heterocyclic group having one or more heteroatom ring members (ring atoms) in at least one ring, and the heteroatom ring members are independently selected from each other From O, S and N. Heteroaryl groups have 5 to 14 ring-forming atoms, including 1 to 13 carbon atoms and 1 to 8 heteroatoms selected from O, S, and N. In some embodiments, a heteroaryl group has 5 to 10 ring-forming atoms, including one to four heteroatoms. Heteroaryl groups may also contain one to three oxo or thiocarbonyl (ie, =S) groups. In some embodiments, a heteroaryl group has 5 to 8 ring-forming atoms, including one, two, or three heteroatoms. For example, a 5-membered heteroaryl group is a monocyclic heteroaryl group as defined above, which has 5 ring-forming atoms in the monocyclic heteroaryl ring; a 6-membered heteroaryl group is a monocyclic heteroaryl group as defined above Group, having 6 ring-forming atoms in a monocyclic heteroaryl ring; 5- to 10-membered heteroaryl is a monocyclic or bicyclic heteroaryl group as defined above, and has 6 ring-forming atoms in a monocyclic or bicyclic heteroaryl ring 5, 6, 7, 8, 9 or 10 ring-forming atoms.

In other embodiments, the compound is one of the following compounds:

(R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide

(R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide;

(R)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)-2-(4-oxo-6-(2-((tetrahydro-2H-pyran-4 -Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)propionamide;

(R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)propionamide ；

(R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3,5-dimethylphenyl)-2-hydroxyethyl)propionamide;

(S)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3,5-dimethylphenyl)-2-hydroxyethyl)propionamide;

(R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-phenylethyl)propionamide;

(S)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-phenylethyl)propionamide;

(R)-2-(6-(5-Chloro-2-((4,4-difluorocyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][ 1,2,4]Triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide;

(S)-2-(6-(5-Chloro-2-((4,4-difluorocyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][ 1,2,4]Triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide;

(2R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)propionamide;

(2S)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)propionamide;

(R)-2-(6-(5-Chloro-2-(isopropylamino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]Three Azin-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide;

(S)-2-(6-(5-Chloro-2-(isopropylamino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]Three Azin-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide;

(R)-2-(6-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2, 1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl ) Propionamide;

(S)-2-(6-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2, 1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl ) Propionamide;

(R)-2-(7-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1,2- a] pyrazine-2-(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide;

(S)-2-(7-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1,2- a] pyrazine-2-(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide;

(2R)-2-(6-(2-((8-oxabicyclo[3.2.1]oct-3-yl)amino)-5-chloropyrimidin-4-yl)-4-oxopyrrolo[ 2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxy Ethyl) propionamide;

(2S)-2-(6-(2-((8-oxabicyclo[3.2.1]oct-3-yl)amino)-5-chloropyrimidin-4-yl)-4-oxopyrrolo[ 2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxy Ethyl) propionamide;

(R)-2-(6-(5-Chloro-2-(((R)-3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy (Phenyl)-2-hydroxyethyl)propionamide;

(S)-2-(6-(5-Chloro-2-(((R)-3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy (Phenyl)-2-hydroxyethyl)propionamide;

(R)-2-(6-(5-chloro-2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f] [1,2,4]Triazine-3(4H)-yl)-N-((S)-1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)propionamide;

(S)-2-(6-(5-chloro-2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f] [1,2,4]Triazine-3(4H)-yl)-N-((S)-1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)propionamide;

(R)-2-(6-(5-Chloro-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy (Phenyl)-2-hydroxyethyl)propionamide;

(S)-2-(6-(5-Chloro-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy (Phenyl)-2-hydroxyethyl)propionamide;

N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(4-oxo-6-(2-((tetrahydro-2H- Pyran-4-yl)amino)pyrimidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)propionamide;

(R)-2-(6-(5-Chloro-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4 -Oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxybenzene Yl)-2-hydroxyethyl)propionamide;

(S)-2-(6-(5-Chloro-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4 -Oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxybenzene Yl)-2-hydroxyethyl)propionamide;

(R)-2-(6-(5-Chloro-2-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1 -f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Propionamide

(S)-2-(6-(5-Chloro-2-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1 -f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Propionamide

(R)-2-(6-(5-Chloro-2-((3,3-difluorocyclic)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1 ,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide;

(S)-2-(6-(5-Chloro-2-((3,3-difluorocyclic)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1 ,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide;

(R)-N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(6-(5-methyl-2-((四Hydrogen-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl) Propionamide

(S)-N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(6-(5-methyl-2-((四Hydrogen-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl) Propionamide

2-(6-(5-Chloro-2-((1-methyl-2-oxopiperidin-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide

2-(6-(2-((1-Acetylpiperidin-4-yl)amino)-5-chloropyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1, 2,4]Triazine-3-(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide;

(R)-2-(6-(5-Chloro-2-(((1r,4R)-4-methoxycyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2, 1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl ) Propionamide;

(S)-2-(6-(5-Chloro-2-(((1r,4S)-4-methoxycyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2, 1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl ) Propionamide;

2-(6-(5-chloro-2-(((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxo Pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)- 2-hydroxyethyl) propionamide;

2-(6-(5-Chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo [2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2- Hydroxyethyl) propionamide;

(R)-2-(6-(5-Chloro-2-(((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4- Oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl) )-2-hydroxyethyl)propionamide;

(S)-2-(6-(5-Chloro-2-(((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4- Oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl) )-2-hydroxyethyl)propionamide;

(R)-2-(7-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1, 2-a]pyrazine-2(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide;

2-(3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)- 1-oxopropan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl )Amino)cyclobutyl)acetic acid;

4-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)-1-oxy Propan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl)amino) Cyclohexane-1-carboxylic acid;

(1R,3S)-3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Amino)-1-oxoprop-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidine- 2-yl)amino)cyclohexane-1-carboxylic acid;

(1R,3S)-3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Amino)-1-oxoprop-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidine- 2-yl)amino)cyclopentane-1-carboxylic acid;

3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)-1-oxy Propan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl)amino) Cyclobutane-1-carboxylic acid;

(R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide;

(R)-2-(7-(5-Chloro-2-(isopropylamino)pyrimidin-4-yl)-1-oxopyrrolo[1,2-a]pyrazine-2(1H)- Yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide;

(2R)-2-(7-(5-chloro-2-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxo Pyrrolo[1,2-a]pyrazine-2(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide

(2R)-2-(7-(5-chloro-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxo Pyrrolo[1,2-a]pyrazine-2(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide

(R)-2-(7-(5-chloro-2-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1 -Oxopyrrolo[1,2-a]pyrazine-2(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl Base) propionamide;

(R)-N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(1-oxo-7-(2-((四Hydrogen-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyrrolo[1,2-a]pyrazine-2(1H)-yl)propionamide;

(R)-2-(7-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1,2- a] pyrazine-2-(1H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide;

(R)-2-(7-(5-chloro-2-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1,2 -a] Pyrazin-2-(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide.

The foregoing compounds can be used to prepare drugs for the prevention or treatment of ERK2-mediated diseases. The ERK2-mediated diseases are cancers, specifically non-small cell lung cancer, pancreatic cancer, colon cancer, gastric cancer, lymphoma or melanoma.

In some embodiments, compounds may exist as stereoisomers, such as atropisomers, racemates, enantiomers, or diastereomers. Conventional techniques for preparing/separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates using, for example, chiral high performance liquid chromatography (HPLC). Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound (e.g., ethanol), or in the case of the compound containing an acidic or basic moiety, with an acid or base (such as tartaric acid). Or 1-phenylethylamine) reaction. The resulting mixture of diastereomers can be separated by chromatography and/or fractional crystallization, and one or both of the diastereomers can be converted into one or more by means well known to those skilled in the art. Corresponding pure enantiomers. Chiral compounds (and their chiral precursors) can be obtained in an enantiomerically enriched form on an asymmetric resin with a mobile phase using chromatography (usually HPLC), the mobile phase is made of a hydrocarbon (usually heptane). Alkane or hexane), containing 0% to 50% 2-propanol (usually 2% to 20%) and 0% to 5% alkylamine (usually 0.1% diethylamine). The eluate is concentrated to obtain an enriched mixture. The stereoisomer aggregates 20 can be separated by conventional techniques known to those skilled in the art. Suitable stereoselective techniques are well known to those of ordinary skill in the art. For compounds of formula (I) containing alkenyl or alkenylene groups, geometric cis/trans (or Z/E) isomers are possible. The cis/trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

The application also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or isomer thereof; a pharmaceutically acceptable carrier or excipient. The pharmaceutically acceptable carrier or excipient may include any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents such as hydrates and solvents. If necessary, the pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, and the like.

This application also provides a compound of formula (II):

Wherein, R ^{8 is} selected from halogen, boronic acid group or pinacol borane; R ^{9 is} selected from C _1-6 alkyl; and Y is selected from C or N.

In some embodiments, formula (II) may be formula (IIa):

Wherein R ^{8 is} selected from halogen, boronic acid group or pinacol borane; R ^{9 is} selected from C _1-6 alkyl; and Y is selected from C or N.

In some embodiments, R ^{8 is} selected from fluorine, chlorine, bromine, iodine, boronic acid or pinacol borane, R ^{9 is} selected from methyl, ethyl, isopropyl or n-butyl; and Y is selected from C or N.

This application also provides a compound of formula (Ⅲ):

Wherein, R ^{11 is} selected from halogen or -NHR ¹ ; R ^{10 is} selected from hydrogen or C _1-6 alkyl; and X, Y, R ¹ and R ² have the meanings defined above.

In some embodiments, formula (III) is formula (IIIa):

Wherein R ^{11 is} selected from halogen or -NHR ¹ ; R ^{10 is} selected from hydrogen or C _1-6 alkyl; and X, Y, R ¹ and R ² have the meanings defined in claim 1.

In some embodiments, R ^{11 is} selected from fluorine, chlorine, bromine, iodine, or -NHR ¹ ; R ^{10 is} selected from hydrogen, methyl, ethyl, isopropyl, or n-butyl; and X, Y, R ¹ and R ² has the meaning defined in claim 1.

The compounds of formula (II), formula (IIa), formula (III), and formula (IIIa) can be used to prepare the aforementioned compound of formula (I).

The compound provided in this application has obvious ERK inhibitor activity, good cell proliferation inhibitory activity, can simultaneously inhibit the phosphorylation of EKR1/2 and downstream pathways, and has obvious cell selectivity and pharmacokinetic properties compared to positive drugs. Advantage.

Detailed ways

The compounds involved in this application can be prepared with reference to the following general methods:

Method I

Reagents and conditions: (a) 2,4-Dinitrophenylhydroxylamine, NaH, DMF, 0℃; (b) N,N-dimethylformamide dimethyl acetal, 60℃, 3h; (c ) LiOH, THF/H ₂ O, 60°C; (d) (R)-2-tert-butyl-2-aminopropionate hydrochloride, HATU, DIPEA, DMF; (e) acetic acid/acetonitrile, 70°C; (f) Diboron pinacol ester, potassium acetate, Pd(dppf)Cl ₂ , dioxane, 90℃; (g) 2,4-dichloro-5-R ² -pyrimidine, Na ₂ CO ₃ , Pd(dppf)Cl ₂ , dioxane, 90℃; (h) TFA, DCM; (i) NH ₂ R ¹ , Na ₂ CO ₃ , dioxane, 90℃ or NH ₂ R ¹ , Pd ₂ (dba) ₃ , Xantphos, Cs ₂ CO ₃ , dioxane, 100°C; (j) HATU, DIPEA, DMF, NHR ³ R ⁴ .

The above synthesis method I is mainly used to synthesize 4-oxopyrrolo[2,1-f][1,2,4]triazine molecules, wherein when R ¹ is an alkyl or cycloalkyl molecule, the synthesis method is NH ₂ R ¹ , Na ₂ CO ₃ , dioxane, 90℃, when R ¹ is aryl or heterocyclic aryl, the synthesis method is NH ₂ R ¹ , Pd ₂ (dba) ₃ , Xantphos, Cs ₂ CO ₃ , dioxane, 100°C.

Method II

Reagents and conditions: (a) 2-bromo-1,1-diethoxyethane, NaH, DMF; (b) LiOH, THF/H ₂ O, 60℃; (c) (R)-2-tert Butyl-2-aminopropionate hydrochloride, HATU, DIPEA, DMF; (d) acetic acid/acetonitrile, 70℃; (e) diboron pinacol ester, potassium acetate, Pd(dppf)Cl ₂ , dioxy Six ring, 90°C; (f) 2,4-Dichloro-5-R ² -pyrimidine, Na ₂ CO ₃ , Pd(dppf)Cl ₂ , dioxane, 90°C; (g) TFA, DCM; (h) NH ₂ R ¹ , Na ₂ CO ₃ , dioxane, 90℃ or NH ₂ R ¹ , Pd ₂ (dba) ₃ , Xantphos, Cs ₂ CO ₃ , dioxane, 100℃; (i ) HATU, DIPEA, DMF, NHR ³ R ⁴ .

The above synthesis method II is mainly used to synthesize 1-oxopyrrolo[1,2-a]pyrazine molecules, wherein when R ¹ is an alkyl or cycloalkyl molecule, the synthesis method is NH ₂ R ¹ , Na ₂ CO ₃ , dioxane, 90℃, when R ¹ is aryl or heterocyclic aryl, the synthesis method is NH ₂ R ¹ , Pd ₂ (dba) ₃ , Xantphos, Cs ₂ CO ₃ , dioxane ,100℃.

Method Ⅲ

Reagents and conditions: (a) tert-butyl 2-bromopropionate, NaH, DMF, 0°C; (b) diboron pinacol ester, potassium acetate, Pd(dppf)Cl ₂ , dioxane, 90°C ; (C) 2,4-Dichloro-5-R ² -pyrimidine, Na ₂ CO ₃ , Pd(dppf)Cl ₂ , dioxane, 90℃; (d) TFA, DCM; (e) NH ₂ R ¹ , Na ₂ CO ₃ , dioxane, 90℃ or NH ₂ R ¹ , Pd ₂ (dba) ₃ , Xantphos, Cs ₂ CO ₃ , dioxane, 100℃; (f) HATU, DIPEA, DMF, NHR ³ R ⁴

The above synthesis method III is mainly used to synthesize racemic 4-oxopyrrolo[2,1-f][1,2,4]triazine molecules, and a single configuration can be obtained after preparation and separation, where R ¹ is The synthesis method of alkyl or cycloalkyl molecules is NH ₂ R ¹ , Na ₂ CO ₃ , dioxane, 90℃, when R ¹ is aryl or heterocyclic aryl, the synthesis method is NH ₂ R ¹ , Pd ₂ (dba) ₃ , Xantphos, Cs ₂ CO ₃ , dioxane, 100°C.

Example 1 (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2 ,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl Base) propionamide (compound 1)

At 0°C, to 4-bromo-2-methoxycarbonylpyrrole (10.00g, 48.80mmol, 1.00eq.) in DMF (500mL) solution was added NaH (11.66g, 58.56mmol, 1.20eq.) and stirred After 30 minutes, 2,4-dinitrophenylhydroxylamine (11.66g, 58.56mmol, 1.20eq.) was added, and after the addition, it was stirred at room temperature for 12 hours. The reaction was diluted with water and ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated sodium chloride (200 mL), dried over MgSO ₄ and concentrated to dryness to obtain Intermediate 1.1 (10.9 g, 94.3% yield).

Intermediate 1.1 (10.00 g, 50.22 mmol, 1.00 eq.) was added to N,N-dimethylformamide dimethyl acetal (150 mL), and then stirred at 60° C. for 3 hours. After the completion of the reaction was monitored by TLC, the solvent was concentrated to obtain Intermediate 1.2 (11.0 g, 88% yield) as a brown oil, which was directly used in the next step without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.95(s,1H), 7.16(d,J=2.2Hz,1H), 6.75(d,J=2.2Hz,1H), 3.68(s, 3H), 2.92 (d, J=32.9 Hz, 6H).

Intermediate 1.2 (11.00 g, 40.13 mmol, 1.00 eq.) was placed in a THF/water mixture (100 mL/50 mL) and _{LiOH.H 2} O (5.05 g, 120.39 mmol, 3.00 eq.) was added thereto. The mixture was then stirred and heated to 60°C for 12 hours. After confirming the completion of the reaction by TLC, the solvent was removed in vacuo, and the residue was neutralized to pH 6-7 with 1.5N HCl. The white solid was filtered, washed with water and dried to obtain Intermediate 1.3 (7 g, yield 67.3%). ¹ H NMR(400MHz,DMSO-d6)δ(ppm) 12.75(s,1H), 8.09(s,1H), 7.26(d,J=2.2Hz,1H), 6.72(d,J=2.2Hz,1H ), 2.94 (d, J=46.4 Hz, 6H).

To a solution of Intermediate 1.3 (3.00g, 11.53mmol, 1.00eq.) in DMF (100mL) was added (R)-2-tert-butyl-2-aminopropionate hydrochloride (2.30g, 12.68mmol, 1.10 eq.) and DIPEA (4.47 g, 34.59 mmol, 3.00 eq.). After stirring for 15 minutes, HATU (4.82 g, 12.68 mmol, 1.10 eq.) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (300 mL) and EtOAc (150 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL). The ether solution was dried (MgSO ₄ ), filtered and concentrated to obtain intermediate 1.4 (3.5 g, 78.4% yield) as a yellow solid, which was used directly in the next step without further purification. ¹ H NMR(400MHz,DMSO-d6)δ(ppm)9.03(d,J=7.0Hz,1H), 8.28(s,1H), 7.38(d,J=2.2Hz,1H), 6.63(d,J = 2.2Hz, 1H), 4.34 (p, J = 7.1Hz, 1H), 3.00 (d, J = 36.9Hz, 6H), 1.42 (s, 9H), 1.34 (d, J = 7.1Hz, 3H).

Intermediate 1.4 (3.50 g, 9.04 mmol, 1.00 eq.) was placed in a mixed solution of acetonitrile (20 mL) and acetic acid (10 mL), and the mixture was stirred at 70°C for 12 hours. The reaction was diluted with water (50 mL) and EtOAc (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with NaHCO ₃ (3×50 mL). The organic phase was dried with MgSO ₄ , filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EA=10/1～3/1) to obtain Intermediate 1.5 (1.8 g, 60% yield) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.19(s,1H), 7.90(d,J=1.8Hz,1H), 7.08(d,J=1.8Hz,1H), 5.11(d, J = 7.3 Hz, 1H), 1.61 (d, J = 7.3 Hz, 3H), 1.39 (s, 9H).

Add diboron pinacol ester (1.60g, 6.31mmol, 1.20eq.), potassium acetate (1.55g) to a solution of intermediate 1.5 (1.80g, 5.26mmol, 1.00eq.) in dioxane (30.0mL) , 15.78mmol, 3.00eq.) and Pd(dppf)Cl ₂ (0.38g, 0.53mmol, 0.10eq.). The reaction was heated to 90°C and stirred under nitrogen for 6 hours. After cooling to room temperature, the solvent was removed in vacuo, the residue was taken in EtOAc (100 mL) and water (100 mL), the organic phase was collected and washed with brine (100 mL). The organic solution was dried with MgSO _4, filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EA=10/1～3/1) to obtain Intermediate 1.6 (1.1 g, 53.9% yield) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6)δ(ppm)8.14(s,1H),7.77(d,J=1.6Hz,1H), 7.04(d,J=1.6Hz,1H), 5.12(d,J = 7.3 Hz, 1H), 2.26-2.20 (m, 1H), 1.61 (d, J = 7.3 Hz, 3H), 1.39 (s, 9H), 1.29 (s, 12H).

Intermediate 1.6 (1.10g, 15.49mmol, 1.00eq.), 2,4,5-trichloropyrimidine (0.78g, 4.25mmol, 1.50eq.), Pd(dppf)Cl ₂ (0.38g, 0.53mmol, 0.10 eq.) and 2.0M Na ₂ CO ₃ (2.8 mL, 5.66 mmol, 2.00 eq.) were added to 20 mL of dioxane, and the mixture was heated to 90° C. and stirred for 6 hours. The reaction was diluted with water (60 mL) and EtOAc (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), and the organic solution was dried with MgSO ₄ , filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EA=10/1～3/1) to obtain Intermediate 1.7 (0.8 g, 72.7% yield) as an off-white solid. ¹ H NMR(400MHz,DMSO-d6)δ(ppm)δ8.91(s,1H), 8.50(d,J=1.9Hz,1H), 8.32(s,1H), 7.68(d,J=1.9Hz , 1H), 5.16 (d, J = 7.3 Hz, 1H), 1.64 (d, J = 7.3 Hz, 3H), 1.41 (s, 9H).

Trifluoroacetic acid (333.51 mg, 29.25 mmol, 15.00 eq.) was added dropwise to a solution of intermediate 1.7 (800.00 mg, 1.95 mmol, 1.00 eq.) in DCM (10 mL), and the mixture was stirred at room temperature for 12 hours, The mixture was concentrated to dryness to obtain Intermediate 1.8 (650 mg, 94.2% yield) as a colorless oil. It was not further purified and used directly in the next step.

Intermediate 1.8 (650.00mg, 1.84mmol, 1.00eq.), 4-aminotetrahydropyran hydrochloride (759.83mg, 5.52mmol, 3.00eq.) and sodium carbonate (2M, 3.7mL, 7.36mmol, 4.00 eq.) was added to 20 mL of dioxane, and the mixture was heated to 90° C. and stirred for 6 hours. The reaction was cooled, hydrochloric acid (1M aqueous solution, 2 mL) was added, and a thick colorless precipitate formed immediately. The slurry was filtered and the filter cake was washed with water (20 mL). The obtained solid was vacuum dried at 40°C to obtain Intermediate 1.9 (600.00 mg, 77.9% yield) as a yellow solid.

DIPEA (279.16mg, 2.16mmol, 3.00eq.) was added to Intermediate 1.9 (300.00mg, 0.72mmol, 1.00eq.) and (2S)-2-amino-2-(5-fluoro-3-methoxy) Phenyl)ethan-1-ol (146.68 mg, 0.79 mmol, 1.10 eq.) in DMF (20 mL). After stirring for 15 minutes, HATU (300.38 mg, 0.79 mmol, 1.10 eq.) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (60 mL) and EtOAc (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried with MgSO ₄ and concentrated. The residue was purified by column chromatography on silica gel, DCM/MeOH=50/1～20/1) to obtain compound 1 (200 mg, 47.6% yield) as an off-white solid. MS: [M+H] ⁺ =586/588. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.82 (s, 1H), 8.46-8.07 (m, 3H), 7.61 (d, J = 1.6 Hz, 1H), 6.88-6.55 (m, 3H) ), 5.52 (d, J = 7.4 Hz, 1H), 4.97 (t, J = 5.5 Hz, 1H), 4.82 (d, J = 7.1 Hz, 1H), 3.92 (dd, J = 29.5, 9.1 Hz, 3H ),3.77(s,3H),3.57(s,2H),3.43(s,1H),1.81(dd,J=43.1,11.4Hz,2H),1.62(t,J=11.9Hz,3H),1.53 (ddd, J=15.5, 12.5, 4.2 Hz, 2H).

Example 2 (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)-4-oxopyrrolo[2 ,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide (compound 2)

Under stirring, dissolve 5-chloro-2-fluoro-4-iodopyridine (3.00g, 11.65mmol, 1.00eq.) and 4-aminotetrahydropyran hydrochloride (3.21g, 23.30mmol, 2.00eq.) In 30mL ethanol. N,N-diisopropylethylamine (4.52g, 34.95mmol, 3.00eq.) was added and reacted at 90°C for 12 hours. The reaction was diluted with water and extracted with EtOAc. The combined organic layer was washed with saturated brine, dried over MgSO ₄ and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EtOAc=5/1～3/1) to obtain Intermediate 2.1 (2.50 g, 64% yield) as a white solid.

Intermediate 2.2 was prepared using a similar synthesis procedure to compound 1.7 in Example 1, with intermediate 2.1 as the starting material. MS: [M+H] ⁺ =552/554. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.22 (s, 1H), 8.10-7.87 (m, 2H), 7.27 (d, J = 1.8 Hz, 1H), 6.72 (s, 1H), 6.67 (d, J = 7.7 Hz, 1H), 5.15 (q, J = 7.3 Hz, 1H), 3.90 (ddd, J = 11.4, 9.2, 5.1 Hz, 3H), 3.57–3.35 (m, 2H), 1.96 -1.78 (m, 2H), 1.63 (d, J = 7.3 Hz, 3H), 1.53-1.48 (m, 1H), 1.41 (s, 9H).

Compound 2 was prepared using a similar synthetic procedure to compound 1 in Example 1, with intermediate 2.2 as the starting material. MS: [M+H] ⁺ =552/554. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.73 (dd, J = 42.9, 8.1 Hz, 1H), 8.16 (d, J = 10.1 Hz, 1H), 8.04 (dd, J = 5.2, 2.9 Hz, 2H), 7.37–7.12(m, 2H), 7.17–6.92(m, 3H), 6.69(dd, J = 10.0, 4.5Hz, 2H), 5.64–5.37(m, 1H), 4.99–4.87( m, 1H), 4.79 (dt, J = 8.1, 4.0 Hz, 1H), 3.56 (dt, J = 8.5, 5.4 Hz, 2H), 3.41 (t, J = 11.5 Hz, 2H), 2.29 (d, J = 12.5 Hz, 3H), 1.87 (d, J = 12.5 Hz, 2H), 1.63 (dd, J = 19.4, 7.4 Hz, 3H), 1.53-1.31 (m, 2H).

Example 3 (R)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)-2-(4-oxo-6-(2-((tetrahydro-2H-pyridine) (Pyran-4-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)propane Amide (Compound 3)

Intermediate 3.1 was prepared by using the similar synthetic steps of compound 2.1 in Example 2 with the starting material 2,4-dichloro-5-(trifluoromethyl)pyrimidine. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.60 (dd, J = 18.5, 7.9 Hz, 2H), 4.11–3.91 (m, 1H), 3.97–3.76 (m, 2H), 3.54–3.34 (m, 2H), 1.80 (dd, J=12.5, 2.0 Hz, 2H), 1.69-1.40 (m, 2H).

Compound 3 was prepared using a similar synthetic procedure to compound 2 in Example 2, with intermediate 3.1 as the starting material. MS: [M+H] ⁺ =586. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.79 (d, J = 6.0 Hz, 1H), 8.63 (d, J = 22.5 Hz, 1H), 8.22 (s, 1H), 8.04 (dd, J = 27.7, 20.4 Hz, 2H), 7.32 (s, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.17-6.86 (m, 3H), 5.53 (q, J = 7.1 Hz, 1H), 4.92 (t, J = 5.4 Hz, 1H), 4.80 (d, J = 6.6 Hz, 1H), 4.06 (dd, J = 16.9, 9.8 Hz, 1H), 3.89 (d, J = 11.4 Hz, 2H), 3.55(t,J=6.7Hz,2H),3.51–3.35(m,2H),2.30(s,3H),1.86(t,J=13.0Hz,2H),1.59(t,J=13.3Hz,3H ), 1.27 (d, J=13.5 Hz, 3H).

Example 4 (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2 ,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl ) Propionamide (Compound 4)

Compound 4 was prepared using a similar synthetic procedure to compound 1 in Example 1, using (2S)-2-amino-2-(3-trifluoromethyl-phenyl)-ethanol as the starting material. MS: [M+H] ⁺ =606/608. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.95 (d, J = 8.0 Hz, 1H), 8.45-8.25 (m, 2H), 8.19 (d, J = 21.8 Hz, 1H), 7.68 ( s,1H),7.65–7.52(m,3H),7.41(d,J=7.7Hz,1H),5.51(dd,J=14.9,7.5Hz,1H),5.03(t,J=5.4Hz,1H ), 4.94(dd,J=13.8,6.0Hz,1H), 4.11–3.90(m,1H), 3.89(d,J=11.1Hz,1H), 3.60(dd,J=14.1,8.3Hz,1H) ,3.43(s,1H),1.91–1.70(m,1H),1.66–1.54(m,1H),1.62–1.40(m,2H).

Example 5 (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2 ,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3,5-dimethylphenyl)-2-hydroxyethyl) Propionamide (compound 5A) and (S)-2-(6-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxo Pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3,5-dimethylphenyl)-2- Hydroxyethyl) propionamide (compound 5B)

DIPEA (279.16mg, 2.16mmol, 3.00eq.) was added to Intermediate 1.9 (300.00mg, 0.72mmol, 1.00eq.) and (2S)-2-amino-2-(3,5-dimethylphenyl) ) Ethan-1-ol (130.54 mg, 0.79 mmol, 1.10 eq.) in DMF (20 mL). After stirring for 15 minutes, HATU (300.38 mg, 0.79 mmol, 1.10 eq.) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (60 mL) and EtOAc (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried with MgSO ₄ and concentrated. The residue was purified by column chromatography on silica gel, DCM/MeOH=50/1～20/1) to obtain 5A (50mg, 12.3% yield, _Rf =0.4, EA) as an off-white solid. MS: [M+H] ⁺ =566/568. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.75(d,J=8.0Hz,1H), 8.33(d,J=20.4Hz,2H), 8.22(d,J=4.6Hz,1H) ,7.60(dd,J=5.9,1.8Hz,1H),7.40(d,J=7.7Hz,1H), 6.89(d,J=10.3Hz,3H),5.52(q,J=7.3Hz,1H) ,4.88(t,J＝5.5Hz,1H), 4.75(dd,J＝13.3,7.3Hz,1H),4.02(dt,J＝17.0,8.5Hz,1H), 3.87(dd,J＝21.5,13.5 Hz,2H),3.63–3.48(m,2H),3.43(s,2H),2.31–2.19(m,3H),2.51(s,6H),1.86(d,J=10.6Hz,2H),1.59 (t, J=11.9 Hz, 3H), 1.53 (dd, J=11.8, 3.7 Hz, 2H).

The residue was purified by column chromatography to obtain 5B (40 mg, 9.8% yield, R _f =0.3, EA) as an off-white solid. MS: [M+H] ⁺ =566/568. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.64 (d, J = 8.2 Hz, 1H), 8.33 (d, J = 19.1 Hz, 2H), 8.18 (s, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.39 (t, J = 9.4 Hz, 1H), 6.87 (d, J = 15.6 Hz, 3H), 5.46 (q, J = 7.3 Hz, 1H), 4.88 (t, J = 5.6Hz, 1H), 4.75 (dd, J = 13.4, 7.5 Hz, 1H), 3.97 (s, 1H), 3.88 (d, J = 11.4 Hz, 2H), 3.55 (qd, J = 11.0, 5.8 Hz, 2H), 3.42 (s, 2H), 2.24 (d, J = 12.5Hz, 4H), 2.51 (s, 6H), 1.86 (d, J = 10.1Hz, 2H), 1.65 (d, J = 7.4Hz, 3H), 1.53 (dd, J=20.1, 9.2 Hz, 2H).

Example 6 (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2 ,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-phenylethyl)propionamide (Compound 6A) and (S) -2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][ 1,2,4)Triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-phenethyl)propionamide (Compound 6B)

DIPEA (279.16mg, 2.16mmol, 3.00eq.) was added to Intermediate 1.9 (300.00mg, 0.72mmol, 1.00eq.) and (2S)-2-amino-2-phenylethanol-1-ol (72.49mg , 0.79mmol, 1.10eq.) in DMF (20mL) solution. After stirring for 15 minutes, HATU (300.38 mg, 0.79 mmol, 1.10 eq.) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (60 mL) and EtOAc (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried with MgSO ₄ and concentrated. The residue was purified by column chromatography on silica gel, DCM/MeOH=50/1～20/1) to obtain 6A (40mg, 9.5% yield, _Rf =0.35, EA) as an off-white solid. MS: [M+H] ⁺ =538/540. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.83 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 20.8 Hz, 2H), 8.21 (s, 1H), 7.61 (d, J=1.7Hz,1H),7.49–7.11(m,6H), 5.67–5.45(m,1H), 4.93(t,J=5.5Hz,1H), 4.92–4.74(m,1H),4.01(dd ,J＝18.3,11.1Hz,1H),3.89(d,J＝11.2Hz,2H),3.57(dd,J＝9.1,4.1Hz,2H),3.43(s,2H),1.87(d,J＝ 11.4Hz, 2H), 1.67–1.55(m,3H), 1.59–1.46(m,2H).

The residue was purified by column chromatography to obtain 6B (40 mg, 9.5% yield, R _f =0.3, EA) as an off-white solid. MS: [M+H] ⁺ =538/540. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.72 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 20.7 Hz, 2H), 8.20 (s, 1H), 7.58 (d, J = 1.6Hz, 1H), 7.49-7.12 (m, 6H), 5.48 (q, J = 7.3 Hz, 1H), 4.91 (dd, J = 17.9, 12.4 Hz, 1H), 4.84 (dd, J = 13.5 ,7.4Hz,1H),4.01(dd,J=20.1,12.9Hz,1H),3.88(d,J=11.2Hz,2H),3.69–3.52(m,2H),3.42(s,2H),1.86 (d, J = 11.2 Hz, 2H), 1.64 (t, J = 20.0 Hz, 3H), 1.60-1.44 (m, 2H).

Example 7 (R)-2-(6-(5-Chloro-2-((4,4-difluorocyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide (Compound 7A) and (S )-2-(6-(5-chloro-2-((4,4-difluorocyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1, 2,4)Triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide (Compound 7B)

Compound 7A was prepared using the similar synthetic steps of compound 1.8 in Example 1 and compound 5A in Example 5, using 4,4-difluorocyclohexylamine hydrochloride as the starting material. MS: [M+H] ⁺ =586/588. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.79 (d, J = 8.0 Hz, 1H), 8.36 (s, 2H), 8.21 (s, 1H), 7.64 (s, 1H), 7.43 ( d, J = 7.7 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.08 (dd, J = 16.6, 8.2 Hz, 3H), 5.53 (q, J = 7.3 Hz, 1H), 4.90 ( t,J=5.5Hz,1H), 4.80(dd,J=13.4,7.1Hz,1H), 4.15–3.89(m,1H), 3.66–3.46(m,2H), 2.30(s,3H),1.99 (dd, J = 30.5, 18.8 Hz, 5H), 1.61 (d, J = 7.4 Hz, 4H).

Compound 7B was prepared using the similar synthetic procedures of compound 1.8 in Example 1 and compound 5B in Example 5. MS: [M+H] ⁺ =586/588. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.69 (d, J = 8.2 Hz, 1H), 8.35 (s, 2H), 8.19 (s, 1H), 7.61 (s, 1H), 7.43 ( d, J = 7.6 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.14-6.96 (m, 3H), 5.47 (d, J = 7.4 Hz, 1H), 4.90 (t, J = 5.6 Hz, 1H), 4.79 (dd, J = 13.5, 7.3 Hz, 1H), 3.98 (t, J = 6.6 Hz, 1H), 3.58 (dt, J = 11.5, 5.7 Hz, 2H), 2.29 (d, J = 12.0 Hz, 3H), 1.99 (dd, J = 31.6, 17.9 Hz, 5H), 1.74-1.57 (m, 4H).

Example 8 (2R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2 ,1-f][1,2,4]triazine-3(4H)-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)propionamide (Compound 8A) and ( 2S)-2-(6-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f ][1,2,4]Triazine-3(4H)-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)propionamide (Compound 8B)

Compound 8A was prepared using a similar synthetic procedure to compound 5A in Example 5, using 2-amino-2-(3-chloro-phenyl)-ethanol as the starting material. MS: [M+H] ⁺ =572/574. ¹ H NMR (400MHz, DMSO-d6) δ (ppm) 8.78 (dd, J = 49.0, 8.0 Hz, 1H), 8.48-8.23 (m, 1H), 8.14 (d, J = 64.8 Hz, 2H), 7.61 (d,J=1.7Hz,1H), 7.54–7.12(m,4H), 6.90(dd,J=4.3,1.5Hz,0.5H), 6.57(dd,J=4.2,2.7Hz,0.5H), 5.60–5.32 (m, 1H), 4.98 (dd, J = 10.9, 5.4 Hz, 1H), 4.83 (dd, J = 15.4, 7.1 Hz, 1H), 3.99 (dd, J = 38.5, 20.0 Hz, 1H) ,3.89(d,J=11.1Hz,2H),3.55(d,J=26.4Hz,2H),3.43(s,1H),1.85(s,2H),1.74-1.51(m,3H),1.54( d, J=8.2 Hz, 2H).

Compound 8B was prepared using a synthetic procedure similar to that of compound 5B in Example 5. MS: [M+H] ⁺ =572/574. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.74 (d, J = 8.1 Hz, 1H), 8.33 (d, J = 19.2 Hz, 2H), 8.19 (s, 1H), 7.87 (d, J=9.3Hz,1H), 7.72–7.53(m,2H), 7.50–7.21(m,4H), 5.44(d,J=7.3Hz,1H), 4.98(t,J=5.5Hz,1H), 4.84(dd,J=14.0,6.5Hz,1H),4.03-3.93(m,1H),3.88(d,J=11.2Hz,2H),3.67-3.51(m,2H),3.43(s,2H) ,3.02(s,3H),2.79(s,3H),1.86(d,J=12.1Hz,2H),1.66(d,J=7.3Hz,3H),1.53(d,J=11.6Hz,2H) .

Example 9 (R)-2-(6-(5-Chloro-2-(isopropylamino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2, 4) Triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (Compound 9A) and ( S)-2-(6-(5-Chloro-2-(isopropylamino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine -3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (Compound 9B)

At 0℃, add 6-bromo-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (40.00g, 186.90mmol, 1.00eq.) in DMF (500mL) To the solution, add NaH (8.97g, 224.28mmol, 1.20eq.), stir for 30 minutes, add tert-butyl 2-bromopropionate (42.98g, 205.59mmol, 1.10eq.) dropwise, and stir at room temperature for 2 hour. The reaction was diluted with water and ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated sodium chloride (200 mL), dried over MgSO ₄ and concentrated to dryness to obtain Intermediate 9.1 (50.0 g, 79.3% yield) as an off-white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.19 (s, 1H), 8.00–7.77 (m, 1H), 7.07 (s, 1H), 5.12 (q, J = 7.0 Hz, 1H), 1.61 (d, J = 7.2 Hz, 3H), 1.40 (d, J = 1.4 Hz, 9H).

To a solution of intermediate 9.1 (50.00g, 146.12mmol, 1.00eq.) in dioxane (500.0mL) was added diboron pinacol ester (44.53g, 175.34mmol, 1.20eq.), potassium acetate (43.02g) , 438.36 mmol, 3.00 eq.) and Pd(dppf)Cl ₂ (10.69 g, 14.61 mmol, 0.10 eq.). The reaction was heated to 90°C and stirred under nitrogen for 6 hours. After cooling to room temperature, the solvent was removed in vacuo, the residue was taken in EtOAc (100 mL) and water (100 mL), the organic phase was collected and washed with brine (100 mL). The organic solution was dried with MgSO _4, filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EA=10/1～3/1) to obtain Intermediate 9.2 (23.0 g, 40.4% yield) as an off-white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.14 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.04 (d, J = 1.6 Hz, 1H), 5.12 (d, J = 7.3 Hz, 1H), 2.26-2.20 (m, 1H), 1.61 (d, J = 7.3 Hz, 3H), 1.39 (s, 7H), 1.29 (s, 10H).

Intermediate 9.2 (10.00g, 25.69mmol, 1.00eq.), 2,4,5-trichloropyrimidine (7.07g, 38.54mmol, 1.50eq.) and 2.0M Na ₂ CO ₃ (25.7mL, 51.38mmol, 2.00eq.) was added to 200mL of dioxane, and the mixture was heated to 90°C and stirred for 6 hours. The reaction was diluted with water (200 mL) and EtOAc (100 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), and the organic solution was dried with MgSO ₄ , filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EA=10/1～3/1) to obtain Intermediate 9.3 (6.7 g, 63.8% yield) as an off-white solid. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)δ8.91(s,1H), 8.50(d,J=1.9Hz,1H), 8.32(s,1H), 7.68(d,J=1.9 Hz, 1H), 5.16 (d, J = 7.3 Hz, 1H), 1.64 (d, J = 7.3 Hz, 3H), 1.41 (s, 9H).

Intermediate 9.3 (500.00mg, 1.22mmol, 1.00eq.), isopropylamine (216.34mg, 3.66mmol, 3.00eq.) and 2.0M Na ₂ CO ₃ (2.5mL, 4.88mmol, 4.00eq.) were added to the two In oxane (20 mL), the mixture was heated to 90°C and stirred for 6 hours. The reaction was diluted with water (60 mL) and EtOAc (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), and the organic solution was dried with MgSO ₄ , filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EA=5/1 to 1/1) to obtain Intermediate 9.4 (300.00 g, 56.8% yield) as an off-white solid.

Trifluoroacetic acid (1180.11 mg, 10.35 mmol, 15.00 eq.) was added dropwise to a solution of intermediate 9.4 (300.00 mg, 0.69 mmol, 1.00 eq.) in DCM (10 mL), and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated to dryness to obtain Intermediate 9.5 (180.00 mg, 69.4% yield) as a pale yellow solid.

Compound 9A uses the similar synthetic procedure of compound 5A in Example 5, starting with intermediate 9.5 and (2S)-2-amino-2-(5-fluoro-3-methoxyphenyl)ethan-1-ol Manufactured from raw materials. MS: [M+H] ⁺ =544/546. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.80 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 15.1 Hz, 2H), 8.23 (s, 1H), 7.61 (d, J = 1.7Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.91-6.56 (m, 3H), 5.52 (q, J = 7.3 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.83 (dd, J = 13.6, 6.4 Hz, 1H), 4.08 (s, 1H), 3.77 (s, 3H), 3.57 (t, J = 5.2 Hz, 2H), 1.63 (d, J = 7.4 Hz, 3H), 1.21 (t, J=13.8 Hz, 6H).

Compound 9B was prepared using a synthetic procedure similar to that of compound 5B in Example 5. MS: [M+H] ⁺ =544/546. ¹ H NMR(400MHz,DMSO)δ8.72(d,J=8.1Hz,1H), 8.46–7.95(m,3H), 7.58(d,J=1.7Hz,1H), 7.24(d,J=7.6 Hz, 1H), 7.02–6.39 (m, 3H), 5.45 (q, J = 7.1 Hz, 1H), 4.97 (t, J = 5.5 Hz, 1H), 4.81 (dd, J = 13.1, 6.9 Hz, 1H ), 4.00 (d, J = 54.0 Hz, 1H), 3.89-3.56 (m, 3H), 3.58 (dd, J = 11.4, 5.7 Hz, 2H), 1.66 (d, J = 7.4 Hz, 2H), 1.21 (t, J=14.8 Hz, 6H).

Example 10 (R)-2-(6-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo [2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2- Hydroxyethyl) propionamide (compound 10A) and (S)-2-(6-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl )-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methyl (Oxyphenyl)-2-hydroxyethyl)propionamide (compound 10B)

Intermediate 9.3 (500.00mg, 1.22mmol, 1.00eq.) was dissolved in 10mL toluene, 1-methyl-1H-pyrazol-5-amine (142.10mg, 1.46mmol, 1.20eq.), cesium carbonate ( 795.00mg, 2.44mmol, 2.00eq.), under the protection of nitrogen, add catalytic amount of Pd ₂ (dba) ₃ , Xantphos after addition, raise the temperature to 100℃, react for 12h, spin dry the reaction solution, add 50mL water, add 50mL EA, the separated aqueous phase was extracted with EA, the combined organic extracts were washed with brine (50 mL), the organic solution was dried with MgSO ₄ , filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, DCM/MeOH=50/1～20/1) to obtain Intermediate 10.1 (300.00 g, 52.3% yield) as an off-white solid.

Compound 10A was prepared using a similar synthesis procedure to compound 9A in Example 9, using intermediate 10.1 as the starting material. MS: [M+H] ⁺ =582/584. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.64(s,1H), 8.88(d,J=7.9Hz,1H), 8.55(s,1H), 8.31(d,J=1.8Hz, 1H), 8.24 (s, 1H), 7.57 (s, 1H), 7.39 (d, J = 1.9 Hz, 1H), 6.83-6.54 (m, 3H), 6.28 (d, J = 1.8 Hz, 1H), 5.52 (d, J = 7.4 Hz, 1H), 4.99 (t, J = 5.5 Hz, 1H), 4.81 (dd, J = 13.4, 6.3 Hz, 1H), 3.77 (s, 3H), 3.70 (s, 3H) ), 3.58 (d, J = 5.3 Hz, 2H), 1.64 (d, J = 7.4 Hz, 3H).

Compound 10B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =582/584. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.62(s,1H), 8.72(d,J=8.1Hz,1H), 8.55(s,1H), 8.31(d,J=1.8Hz, 1H), 8.22 (s, 1H), 7.52 (d, J = 20.3 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 6.83-6.55 (m, 3H), 6.28 (d, J = 1.6 Hz, 1H), 5.44 (q, J = 7.2 Hz, 1H), 4.96 (t, J = 5.6 Hz, 1H), 4.81 (dd, J = 13.3, 6.8 Hz, 1H), 3.76 (d, J = 6.9 Hz, 3H), 3.70 (s, 3H), 3.58 (dd, J = 11.4, 5.5 Hz, 2H), 1.66 (d, J = 7.4 Hz, 3H).

Example 11 (R)-2-(7-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1 ,2-a)pyrazine-2-(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (compound 11A) and (S)-2-(7-(5-chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1 ,2-a)pyrazine-2-(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (compound 11B)

At 0°C, to a 500mL DMF solution of 4-bromo-2-methoxycarbonylpyrrole (30.00g, 147.04mmol, 1.00eq.) was added NaH (7.06g, 176.45mmol, 1.20eq.) and stirred for 30 minutes , Bromoacetaldehyde diethyl acetal (31.86g, 161.74mmol, 1.10eq.) was added dropwise, after the addition, stirred at room temperature for 12 hours. The reaction was diluted with water and ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate (2×200 mL). The combined organic extracts were washed with saturated sodium chloride (200 mL), dried over MgSO ₄ and concentrated to dryness to give intermediate 11.1 (33.0 g, 70.2% yield). ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.16 (d, J = 1.4 Hz, 1H), 6.81 (d, J = 1.5 Hz, 1H), 4.64 (t, J = 5.3 Hz, 1H) ,3.77(s,3H),3.69–3.56(m,2H),3.52(dd,J=9.5,7.0Hz,2H), 3.45(d,J=5.3Hz,2H),1.13(t,J=7.0 Hz, 6H).

Intermediate 11.1 (33.00 g, 103.06 mmol, 1.00 eq.) was placed in a THF/water mixture (200 mL/100 mL) and _{LiOH.H 2} O (12.97 g, 309.18 mmol, 3.00 eq.) was added thereto. The mixture was then stirred and heated to 60°C for 12 hours. After confirming the completion of the reaction by TLC, the solvent was removed in vacuo, and the residue was neutralized to pH 6-7 with 1.5N HCl. The white solid was filtered, washed with water and dried to obtain intermediate 11.2 (20.2 g, yield 63.5%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 12.59 (S, 1H), 7.19 (d, J = 1.9 Hz, 1H), 6.82 (d, J = 1.9 Hz, 1H), 4.64 (t, J = 5.4Hz, 1H), 4.34 (d, J = 5.4 Hz, 2H), 3.60 (dd, J = 9.6, 7.1 Hz, 2H), 3.35 (dd, J = 9.6, 7.0 Hz, 2H), 1.04 ( t, J=7.0 Hz, 6H).

To a solution of intermediate 11.2 (20.20g, 65.98mmol, 1.00eq.) in DMF (300mL) was added (R)-2-tert-butyl-2-aminopropionate hydrochloride (13.18g, 72.58mmol, 1.10 eq.) and DIPEA (25.58 g, 197.94 mmol, 3.00 eq.). After stirring for 15 minutes, HATU (27.60 g, 72.58 mmol, 1.10 eq.) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (300 mL) and EtOAc (150 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL). The ether solution was dried (MgSO ₄ ), filtered and concentrated to obtain intermediate 11.3 (23.5 g, 83.9% yield) as a yellow solid, which was used directly in the next step without further purification. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)7.26(dd,J=4.6,2.0Hz,1H), 6.88(dd,J=5.2,2.0Hz,1H), 4.64(dd,J=5.3 ,2.4Hz,1H), 4.35(d,J=5.4Hz,2H),4.22(d,J=7.1Hz,1H), 3.65–3.59(m,3H), 3.34(dd,J=11.5,4.6Hz , 3H), 1.27 (t, J = 7.1 Hz, 2H), 1.12 (d, J = 7.6 Hz, 8H), 1.04 (t, J = 7.0 Hz, 6H).

Intermediate 11.3 (23.50 g, 54.23 mmol, 1.00 eq.) was placed in a mixed solution of acetonitrile (60 mL) and acetic acid (30 mL), and the mixture was stirred at 70°C for 12 hours. The reaction was diluted with water (50 mL) and EtOAc (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with NaHCO ₃ (3×50 mL). The organic phase was dried with MgSO ₄ , filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EA=10/1～3/1) to obtain intermediate 11.4 (12 g, 64.8% yield) as an off-white solid. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 7.64 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 6.0 Hz, 1H), 6.99 (d, J = 1.2 Hz, 1H) , 6.89 (d, J = 6.0 Hz, 1H), 5.14 (q, J = 7.3 Hz, 1H), 1.52 (d, J = 7.3 Hz, 3H), 1.39 (s, 9H).

To a solution of intermediate 11.4 (12.00g, 35.17mmol, 1.00eq.) in dioxane (150.0mL) was added diboron pinacol ester (10.72g, 42.20mmol, 1.20eq.), potassium acetate (10.35g) , 105.51mmol, 3.00eq.) and Pd(dppf)Cl ₂ (2.57g, 3.52mmol, 0.10eq.). The reaction was heated to 90°C and stirred under nitrogen for 6 hours. After cooling to room temperature, the solvent was removed in vacuo, the residue was taken in EtOAc (200 mL) and water (200 mL), the organic phase was collected and washed with brine (200 mL). The organic solution was dried with MgSO _4, filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EA=10/1～3/1) to obtain Intermediate 11.5 (7.5 g, 55.15% yield) as an off-white solid. ¹ H NMR(400MHz, DMSO-d ₆ )δ(ppm) 7.68(d,J=1.5Hz,1H), 7.40(d,J=5.9Hz,1H), 7.02(d,J=0.7Hz,1H) ,6.83(d,J=6.1Hz,1H), 5.14(q,J=7.3Hz,1H), 1.52(t,J=8.5Hz,3H), 1.38(s,9H), 1.29(d,J= 8.4Hz, 12H).

Intermediate 11.5 (7.50g, 15.93mmol, 1.00eq.), 2,4,5-trichloropyrimidine (4.38g, 23.89mmol, 1.50eq.), Pd(dppf)Cl ₂ (0.38g, 0.53mmol, 0.10 eq.) and 2.0M Na ₂ CO ₃ (15.9 mL, 31.86 mmol, 2.00 eq.) were added to 50 mL of dioxane, and the mixture was heated to 90° C. and stirred for 6 hours. The reaction was diluted with water (60 mL) and EtOAc (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), and the organic solution was dried with MgSO ₄ , filtered, and concentrated to dryness. The residue was purified by column chromatography (silica gel, PE/EA=10/1～3/1) to obtain Intermediate 11.6 (5.0 g, 76.9% yield) as an off-white solid.

Trifluoroacetic acid (20.88g, 183.15mmol, 15.00eq.) was added dropwise to a solution of intermediate 11.6 (5.00g, 12.21mmol, 1.00eq.) in DCM (50mL), and the mixture was stirred at room temperature for 12 hours. The mixture was concentrated to dryness to obtain intermediate 11.7 (3.80 g, 88.2% yield) as a colorless oil. It was not further purified and used directly in the next step.

Intermediate 11.7 (3.80g, 10.76mmol, 1.00eq.), 4-aminotetrahydropyran hydrochloride (4.44g, 32.28mmol, 3.00eq.) and sodium carbonate (2M, 21.5mL, 43.04mmol, 4.00 eq.) was added to dioxane (30 mL), and the mixture was heated to 90°C and stirred for 6 hours. The reaction was cooled, hydrochloric acid (1M aqueous solution, 10 mL) was added, and a thick colorless precipitate formed immediately. The slurry was filtered and the filter cake was washed with water (50 mL). The obtained solid was vacuum dried at 40°C to obtain Intermediate 11.8 (3.90 g, 86.6% yield) as a yellow solid.

DIPEA (3.62g, 27.99mmol, 3.00eq.) was added to Intermediate 11.8 (3.90g, 9.33mmol, 1.00eq.) and (2S)-2-amino-2-(5-fluoro-3-methoxy) Phenyl)ethan-1-ol (1.90 g, 10.26 mmol, 1.10 eq.) in DMF (20 mL). After stirring for 15 minutes, HATU (3.90 g, 10.26 mmol, 1.10 eq.) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was diluted with water (60 mL) and EtOAc (30 mL). The phases were separated and the aqueous phase was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (50 mL), dried with MgSO ₄ and concentrated. After chiral separation, compounds 11A and 11B were prepared.

Column: waters SFC200

Column specification: ChiralPak AS, 250×30mm I.D., 5μm

Injection volume: Dissolve the compound in 150mL MEOH, each injection of 17mL

Mobile phase: A is CO ₂ , B is methanol (0.1% NH ₃ H ₂ O)

Flow rate: 70mL/min

Wavelength: UV 254nm

Compound 11A (4.2 g, 77.06% yield) has a retention time of 3.87 min, ee>98%, and is an off-white solid. MS: [M+H] ⁺ =585/587. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.64 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 15.9 Hz, 2H), 7.62 (s, 1H), 7.51 (d, J = 6.1Hz, 1H), 7.35 (d, J = 7.6Hz, 1H), 6.96 (d, J = 6.2Hz, 1H), 6.83-6.42 (m, 3H), 5.53 (q, J = 7.2Hz, 1H), 4.91 (t, J = 5.5 Hz, 1H), 4.81 (dd, J = 14.0, 6.3 Hz, 1H), 3.93 (d, J = 16.0 Hz, 1H), 3.89 (d, J = 11.2 Hz, 2H), 3.77 (s, 3H), 3.56 (t, J = 5.9 Hz, 2H), 3.43 (s, 2H), 1.87 (d, J = 11.3 Hz, 2H), 1.53 (d, J = 15.7 Hz, 2H), 1.50(d, J=7.3Hz, 3H).

Compound 11B (0.2 g, 3.6% yield) has a retention time of 4.61 min, ee>98%, and is an off-white solid. MS: [M+H] ⁺ =585/587. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.56 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 13.2 Hz, 2H), 7.61 (d, J = 1.0 Hz, 1H) ,7.51(d,J=6.1Hz,1H), 7.36(d,J=7.6Hz,1H), 6.88(d,J=6.1Hz,1H), 6.78–6.53(m,3H), 5.48(q, J = 7.1Hz, 1H), 4.92 (t, J = 5.7 Hz, 1H), 4.81 (dd, J = 13.8, 6.5 Hz, 1H), 4.02-3.83 (m, 3H), 3.75 (d, J = 13.8 Hz, 3H), 3.64–3.50 (m, 2H), 3.44 (d, J = 10.8 Hz, 2H), 1.87 (d, J = 9.9 Hz, 2H), 1.54 (t, J = 11.2 Hz, 5H).

Example 12 (2R)-2-(6-(2-((8-oxabicyclo[3.2.1]oct-3-yl)amino)-5-chloropyrimidin-4-yl)-4-oxo Pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)- 2-Hydroxyethyl)propionamide (Compound 12A) and (2S)-2-(6-(2-((8-oxabicyclo[3.2.1]oct-3-yl)amino)-5-chloropyrimidine -4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro -5-methoxyphenyl)-2-hydroxyethyl)propionamide (compound 12B)

Compound 12A was prepared using a similar synthetic procedure to compound 9A in Example 9, using 8-oxabicyclo[3.2.1]octane-3-amine hydrochloric acid as the starting material. MS: [M+H] ⁺ =612/614. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.80 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 22.2 Hz, 2H), 8.22 (s, 1H), 7.60 (d, J = 1.5Hz, 1H), 7.30 (s, 1H), 6.71 (dd, J = 15.7, 6.9 Hz, 3H), 5.51 (q, J = 7.3 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.83 (dd, J = 13.6, 6.4 Hz, 1H), 4.36 (s, 2H), 4.22 (s, 1H), 3.77 (s, 3H), 3.58 (d, J = 5.6 Hz, 2H), 1.92 (d, J=56.6 Hz, 6H), 1.62 (t, J=9.8 Hz, 3H), 1.59 (s, 2H).

Compound 12B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =612/614. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.71 (d, J = 8.0 Hz, 1H), 8.46-8.21 (m, 2H), 8.24-8.05 (m, 1H), 7.57 (s, 1H) ), 7.31 (d, J = 12.3 Hz, 1H), 6.85-6.57 (m, 3H), 5.44 (q, J = 7.2 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.81 (dd ,J=13.2,6.6Hz,1H),4.36(s,2H),4.21(s,1H),3.75(s,3H),3.66-3.47(m,2H),1.83(s,6H),1.65( t, J = 9.9 Hz, 3H), 1.59 (t, J = 11.8 Hz, 2H).

Example 13 (R)-2-(6-(5-Chloro-2-(((R)-3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidine-4- Yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5- Methoxyphenyl)-2-hydroxyethyl)propionamide (compound 13A) and (S)-2-(6-(5-chloro-2-(((R)-3,3-dimethyltetra Hydrogen-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl) -N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (Compound 13B)

Compound 13A was prepared using a similar synthetic procedure to compound 9A in Example 9, using 4-amino-3,3-dimethyltetrahydropyran hydrochloride as the starting material. MS: [M+H] ⁺ =614/616. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.80 (d, J = 8.0 Hz, 1H), 8.34 (s, 2H), 8.23 (s, 1H), 7.63 (s, 1H), 7.15 ( s, 1H), 6.71 (dd, J = 14.9, 6.3 Hz, 3H), 5.52 (q, J = 7.3 Hz, 1H), 4.95 (t, J = 5.4 Hz, 1H), 4.82 (dd, J = 13.6 ,6.4Hz,1H),3.89(d,J=10.3Hz,1H),3.77(s,3H),3.57(dd,J=8.9,3.8Hz,2H),3.43(d,J=11.2Hz,2H ),3.19(s,1H),1.79–1.68(m,1H),1.63(d,J=7.4Hz,3H),1.57(s,1H),0.98(s,3H),0.81(s,3H) .

Compound 13B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =614/616. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.71 (d, J = 8.0 Hz, 1H), 8.33 (s, 2H), 8.20 (s, 1H), 7.61 (s, 1H), 7.15 ( s, 1H), 6.77–6.60 (m, 3H), 5.45 (q, J = 7.2 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.81 (dd, J = 13.2, 6.8 Hz, 1H ), 3.89 (d, J = 10.0Hz, 1H), 3.75 (s, 3H), 3.58 (dd, J = 11.4, 5.7 Hz, 2H), 3.43 (d, J = 11.2 Hz, 2H), 3.18 (s ,1H),1.78–1.70(m,1H),1.66(d,J=7.3Hz,3H),1.58(d,J=11.6Hz,1H),0.98(s,3H),0.80(s,3H) .

Example 14 (R)-2-(6-(5-Chloro-2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1 -f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)propionamide (Compound 14A) and (S)-2-(6-(5-chloro-2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-4-oxopyrrolo(2 ,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl) Propionamide (Compound 14B)

Compound 14A was prepared using a similar synthetic procedure to compound 9A in Example 9, using 2-chloro-4-fluoro-aniline as the starting material. The preparation method is the same as in Example 10, the retention time is 3.54 min, ee=99%, and it is an off-white solid. MS: [M+H] ⁺ =630/632. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 9.21 (s, 1H), 8.70 (d, J = 8.1 Hz, 1H), 8.49 (s, 1H), 8.26 (d, J = 1.8 Hz, 1H), 8.20 (s, 1H), 7.70 (dd, J = 9.0, 5.8 Hz, 1H), 7.56–7.49 (m, 2H), 7.30–7.23 (m, 1H), 6.76–6.64 (m, 3H) ,5.43(q,J=7.3Hz,1H), 4.95(t,J=5.5Hz,1H), 4.81(dd,J=13.4,7.0Hz,1H), 3.75(s,3H),3.58(dd, J = 11.4, 5.9 Hz, 2H), 1.66 (d, J = 7.4 Hz, 3H).

Compound 14B was prepared using the similar synthetic procedure of compound 9B in Example 9. The preparation method was the same as that in Example 10, the retention time was 2.85 min, and ee=100%. MS: [M+H] ⁺ =630/632. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)9.21(s,1H), 8.79(d,J=8.0Hz,1H), 8.49(s,1H), 8.27(d,J=1.8Hz, 1H), 8.23 (s, 1H), 7.70 (dd, J = 9.0, 5.8 Hz, 1H), 7.54 (td, J = 4.9, 3.0 Hz, 2H), 7.32-7.24 (m, 1H), 6.76-6.67 (m,3H),5.51 (q,J=7.3Hz,1H), 4.95(s,1H), 4.82(dd,J=13.8,6.3Hz,1H), 3.77(s,3H),3.57(d, J = 5.2 Hz, 2H), 1.63 (d, J = 7.4 Hz, 3H).

Example 15 (R)-2-(6-(5-Chloro-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidine-4- Yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5- Methoxyphenyl)-2-hydroxyethyl)propionamide (compound 15A) and (S)-2-(6-(5-chloro-2-(((R)-2,2-dimethyltetra Hydrogen-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl) -N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (Compound 15B)

Compound 15A was prepared using a similar synthetic procedure to compound 9A in Example 9, using 4-amino-2,2-dimethyltetrahydropyran hydrochloride as the starting material. MS: [M+H] ⁺ =614/616. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.85 (d, J = 7.9 Hz, 1H), 8.33 (d, J = 20.8 Hz, 2H), 8.22 (s, 1H), 7.61 (s, 1H), 7.31 (s, 1H), 6.71 (dd, J = 16.2, 7.0 Hz, 3H), 5.51 (q, J = 7.1 Hz, 1H), 4.98 (t, J = 5.5 Hz, 1H), 4.82 ( dd, J = 13.4, 6.4 Hz, 1H), 4.13 (s, 1H), 3.77 (s, 3H), 3.68 (s, 2H), 3.58 (d, J = 5.6 Hz, 2H), 3.38 (s, 1H) ), 1.83 (d, J = 11.1 Hz, 1H), 1.64 (d, J = 7.3 Hz, 3H), 1.42 (s, 1H), 1.16 (s, 3H), 1.11 (s, 3H).

Compound 15B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =614/616. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.84 (s, 1H), 8.32 (d, J = 18.6 Hz, 2H), 8.19 (s, 1H), 7.58 (s, 1H), 7.30 ( s,1H),6.79–6.58(m,3H),5.45(s,1H),5.03(s,1H),4.80(s,1H),4.08(d,J=33.0Hz,2H),3.75(s ,3H), 3.68(s, 2H), 3.59(s, 2H), 1.83(s, 1H), 1.68(s, 3H), 1.42(s, 1H), 1.25(s, 3H), 1.15(s, 3H).

Example 16 N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(4-oxo-6-(2-((tetrahydro -2H-pyran-4-yl)amino)pyrimidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)propionamide (compound 16)

The synthetic method of compound 16 is similar to that of compound 9, and it is prepared with 2,4-dichloropyrimidine as the starting material. MS: [M+H] ⁺ =552. ¹ H NMR(400MHz,DMSO-d6)δ(ppm)8.76(dd,J=37.2,8.1Hz,1H), 8.26(dd,J=5.0,2.7Hz,2H), 8.17(d,J=12.4Hz ,1H),7.50(dd,J＝10.7,1.7Hz,1H),7.06(dd,J＝7.5,4.9Hz,2H),6.83-6.53(m,3H),5.49(dq,J＝27.5,7.2 Hz, 1H), 4.96 (t, J = 5.4 Hz, 1H), 4.82 (dt, J = 12.9, 6.4 Hz, 1H), 4.05-3.99 (m, 1H), 3.88 (d, J = 11.3 Hz, 2H ), 3.76 (d, J = 7.1Hz, 3H), 3.63-3.50 (m, 2H), 3.43 (s, 2H), 1.86 (d, J = 11.4Hz, 2H), 1.64 (dd, J = 11.8, 7.4 Hz, 3H), 1.54 (dd, J=19.9, 11.1 Hz, 2H).

Example 17 (R)-2-(6-(5-Chloro-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl )-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methyl Oxyphenyl)-2-hydroxyethyl)propionamide (compound 17A) and (S)-2-(6-(5-chloro-2-(((3S,4R)-3-methyltetrahydro- 2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N -((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (Compound 17B)

Compound 17A was prepared using a similar synthetic procedure to compound 9A in Example 9, using (3R,4S)-3-methyl-piperidin-4-ylamine hydrochloride as the starting material. MS: [M+H] ⁺ =600/602. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.81 (d, J = 8.0 Hz, 1H), 8.33 (s, 2H), 8.22 (s, 1H), 7.61 (d, J = 1.8 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 6.78-6.62 (m, 3H), 5.52 (q, J = 7.3 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.82 ( dd, J = 13.7, 6.3 Hz, 1H), 3.89 (d, J = 7.9 Hz, 1H), 3.81 (dd, J = 11.6, 4.4 Hz, 1H), 3.77 (s, 3H), 3.73–3.67 (m ,1H),3.57(dt,J=7.4,3.8Hz,2H),3.43(s,1H),1.86(s,1H),1.80–1.71(m,1H),1.64(d,J=7.4Hz, 3H), 1.50 (ddd, J = 24.0, 12.4, 4.5 Hz, 1H), 0.80 (d, J = 6.5 Hz, 3H).

Compound 17B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =600/602. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.71 (d, J = 7.6 Hz, 1H), 8.32 (s, 2H), 8.19 (s, 1H), 7.58 (s, 1H), 7.33 ( d,J=8.4Hz,1H), 6.70(dd,J=20.5,10.5Hz,3H), 5.45(d,J=7.2Hz,1H), 4.95(s,1H), 4.81(d,J=6.3 Hz, 1H), 3.88 (d, J = 8.7 Hz, 1H), 3.83–3.78 (m, 1H), 3.75 (s, 3H), 3.58 (d, J = 5.3 Hz, 2H), 3.40 (s, 1H) ),3.08(s,1H),1.86(s,1H),1.79–1.71(m,1H),1.66(d,J=7.1Hz,3H), 1.50(d,J=8.3Hz,1H),0.80 (d, J=6.3 Hz, 3H).

Example 18 (R)-2-(6-(5-Chloro-2-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[ 2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxy Ethyl) propionamide (compound 18A) and (S)-2-(6-(5-chloro-2-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)- 4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy (Phenyl)-2-hydroxyethyl)propionamide (Compound 18B)

Compound 18A was prepared using a similar synthetic procedure to compound 9A in Example 9, using (1S,3S)-3-aminocyclopentan-1-ol hydrochloride as the starting material. MS: [M+H] ⁺ =586/588. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.79 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 8.7 Hz, 2H), 8.22 (s, 1H), 7.61 (d, J = 1.4Hz, 1H), 7.28 (d, J = 6.9 Hz, 1H), 6.77–6.65 (m, 3H), 5.52 (q, J = 7.3 Hz, 1H), 4.95 (t, J = 5.5 Hz, 1H), 4.82(dd,J=13.7,6.4Hz,1H), 4.63(d,J=4.0Hz,1H), 4.27-4.09(m,2H), 3.77(s,3H),3.57(dd,J =9.1,3.9Hz,2H),2.22(s,1H),1.95(s,1H),1.81–1.66(m,2H),1.63(d,J=7.4Hz,3H),1.53–1.42(m, 1H).

Compound 18B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =586/588. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.70 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 9.8 Hz, 2H), 8.19 (s, 1H), 7.59 (d, J=1.6Hz,1H), 7.28(d,J=7.0Hz,1H), 6.76–6.65(m,4H), 5.45(q,J=7.3Hz,1H), 4.95(t,J=5.6Hz, 1H), 4.83–4.75(m,1H), 4.63(d,J=4.1Hz,1H), 4.14(d,J=4.5Hz,2H), 3.64–3.48(m,3H), 2.22(s,1H ),1.94(s,1H),1.80–1.70(m,1H),1.66(d,J=7.3Hz,3H),1.59(dd,J=7.7,3.7Hz,1H),1.53–1.44(m, 1H).

Example 19 (R)-2-(6-(5-Chloro-2-((3,3-difluorocyclic)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f ][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (Compound 19A) and (S)-2-(6-(5-chloro-2-((3,3-difluorocyclic)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1 -f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Propionamide (Compound 19B)

Compound 19A was prepared using a similar synthetic procedure to compound 9A in Example 9, using 3,3-difluorocyclobutylamine hydrochloride as the starting material. MS: [M+H] ⁺ =592/594. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.90–8.81(m,1H),8.55–8.26(m,2H),8.23(s,1H),7.90(d,J=6.3Hz,1H ), 7.65 (d, J = 16.6Hz, 1H), 6.80-6.60 (m, 3H), 5.53 (q, J = 7.0 Hz, 1H), 4.98 (t, J = 5.4 Hz, 1H), 4.82 (dd ,J＝13.3,6.6Hz,1H),4.26(s,1H),3.77(s,3H),3.56(t,J＝14.2Hz,2H),2.99(s,2H),2.69(d,J＝ 10.9 Hz, 2H), 1.64 (d, J=7.3 Hz, 3H).

Compound 19B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =592/594. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.71 (d, J = 8.1 Hz, 1H), 8.46-8.21 (m, 2H), 8.23 (d, J = 20.3 Hz, 1H), 7.90 ( d,J=6.2Hz,1H), 7.62(d,J=14.9Hz,1H), 6.70(dd,J=19.2,10.0Hz,3H), 5.45(q,J=7.1Hz,1H), 4.96( t,J=5.5Hz,1H), 4.81(dd,J=13.4,6.8Hz,1H), 4.26(s,1H), 3.76(s,3H), 3.66–3.49(m,2H), 2.99(s , 2H), 2.77–2.58 (m, 2H), 1.66 (d, J=7.3 Hz, 3H).

Example 20 (R)-N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(6-(5-methyl-2- ((Tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H) -Yl)propionamide (compound 20A) and (S)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(6-( 5-methyl-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4] Triazine-3(4H)-yl)propionamide (Compound 20B)

Compound 20A was prepared using a similar synthetic procedure to compound 9A in Example 9, using 2,4-dichloro-5-methylpyrimidine as the starting material. MS: [M+H] ⁺ =566. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.81 (d, J = 8.0 Hz, 1H), 8.13 (dd, J = 33.5, 9.1 Hz, 3H), 7.43 (d, J = 1.7 Hz, 1H), 6.83 (d, J = 7.7 Hz, 1H), 6.71 (dd, J = 15.3, 6.7 Hz, 3H), 5.52 (q, J = 7.3 Hz, 1H), 4.96 (t, J = 5.5 Hz, 1H), 4.82(dd,J=13.6,6.3Hz,1H),4.03-3.93(m,1H),3.92-3.84(m,2H),3.77(s,3H),3.57(t,J=5.4Hz , 2H), 3.42 (t, J = 10.9 Hz, 2H), 2.31 (s, 3H), 1.87 (d, J = 11.4 Hz, 2H), 1.63 (d, J = 7.4 Hz, 3H), 1.52 (ddd , J=15.5, 12.4, 4.2 Hz, 2H).

Compound 20B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =566. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.71(d,J=8.1Hz,1H), 8.15(d,J=7.3Hz,2H), 8.08(d,J=1.5Hz,1H) ,7.40(d,J=1.7Hz,1H), 6.83(d,J=7.7Hz,1H), 6.77–6.65(m,3H), 5.45(q,J=7.3Hz,1H), 4.96(t, J = 5.6Hz, 1H), 4.81 (dd, J = 13.4, 6.8Hz, 1H), 4.00–3.93 (m, 1H), 3.88 (d, J = 11.2Hz, 2H), 3.75 (s, 3H), 3.65–3.53(m,2H),3.42(t,J=10.9Hz,2H),2.30(s,3H),1.86(d,J=11.4Hz,2H),1.66(d,J=7.4Hz,3H ), 1.58–1.46 (m, 2H).

Example 21 2-(6-(5-Chloro-2-((1-methyl-2-oxopiperidin-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2 ,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl Base) propionamide (compound 21)

The synthetic method of compound 21 is similar to that of compound 1, and it is prepared with 4-amino-1-methyl-piperidin-2-one as the starting material. MS: [M+H] ⁺ =613/615. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.76 (dd, J = 39.1, 7.6 Hz, 1H), 8.49-8.04 (m, 3H), 7.56 (dd, J = 41.7, 8.7 Hz, 2H ), 7.07–6.53(m,4H), 5.48(dd,J=28.7,7.3Hz,1H), 4.96(s,1H), 4.81(s,1H), 3.89–3.65(m,3H), 3.54( d, J = 22.0Hz, 2H), 2.85 (d, J = 10.6Hz, 3H), 2.60 (s, 1H), 2.30 (dd, J = 16.7, 9.1Hz, 1H), 2.09 (s, 1H), 1.80 (s, 1H), 1.72–1.54 (m, 3H).

Example 22 2-(6-(2-((1-Acetylpiperidin-4-yl)amino)-5-chloropyrimidin-4-yl)-4-oxopyrrolo[2,1-f] [1,2,4]Triazine-3-(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (Compound 22)

The synthetic method of compound 22 is similar to that of compound 1, and 1-(4-amino-piperidin-1-yl)-ethanone is prepared as the starting material. MS: [M+H] ⁺ =627. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.76 (dd, J = 39.1, 7.6 Hz, 1H), 8.29 (dd, J = 58.7, 13.5 Hz, 3H), 7.61 (d, J = 10.2 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 6.69 (d, J = 28.2 Hz, 4H), 5.48 (dd, J = 28.7, 7.3 Hz, 1H), 4.96 (s, 1H), 4.81(s,1H),3.93-3.65(m,3H),3.54(d,J=22.0Hz,2H), 2.85(d,J=10.6Hz,3H), 2.60(s,1H), 2.30(dd , J=16.7, 9.1 Hz, 2H), 2.09 (s, 1H), 1.80 (s, 1H), 1.68-1.42 (m, 3H).

Example 23 (R)-2-(6-(5-Chloro-2-(((1r,4R)-4-methoxycyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo [2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2- Hydroxyethyl)propionamide (compound 23A) and (S)-2-(6-(5-chloro-2-(((1r,4S)-4-methoxycyclohexyl)amino)pyrimidin-4-yl )-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methyl (Oxyphenyl)-2-hydroxyethyl)propionamide (compound 23B)

Compound 23A was prepared using a similar synthetic procedure to compound 9A in Example 9, using trans-4-methoxy-cyclohexyl-1-aminohydrochloride as the starting material. MS: [M+H] ⁺ =614/616. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.80 (d, J = 8.1 Hz, 1H), 8.33-8.22 (m, 3H), 7.59 (d, J = 1.8 Hz, 1H), 7.27 ( d,J=7.6Hz,1H),6.74-6.68(m,3H),5.51(q,J=7.3Hz,1H), 4.96(s,1H), 4.82(dd,J=13.5,6.9Hz,1H ), 3.76(s, 3H), 3.57–3.56(m, 2H), 3.23(s, 3H), 3.12(s, 1H), 2.00(dd, J=18.6, 13.1Hz, 3H), 1.63(d, J = 7.4 Hz, 3H), 1.26 (dd, J = 22.7, 12.9 Hz, 4H).

Compound 23B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =614/616. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.71 (d, J = 8.1 Hz, 1H), 8.48-7.88 (m, 3H), 7.57 (d, J = 1.8 Hz, 1H), 7.27 ( d,J=7.6Hz,1H), 6.91–6.38(m,3H), 5.44(q,J=7.3Hz,1H), 4.96(s,1H), 4.81(dd,J=13.5,6.9Hz,1H ), 3.75(s, 3H), 3.67–3.45(m, 2H), 3.25(s, 3H), 3.13(s, 1H), 2.00(dd, J=18.6, 13.1Hz, 3H), 1.66(d, J = 7.4 Hz, 3H), 1.29 (dd, J = 22.7, 12.9 Hz, 4H).

Example 24 2-(6-(5-Chloro-2-(((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4 -Oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxybenzene (Yl)-2-hydroxyethyl)propionamide (Compound 24)

Compound 24 was prepared using a similar synthesis procedure in Example 9 using (3S,4R)-4-amino-3-methoxytetrahydropyran hydrochloride as the starting material. MS: [M+H] ⁺ =616/618. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.76(dd,J=37.8,8.0Hz,1H),8.45-8.12(m,3H),7.60(dd,J=11.5,1.8Hz,1H ),7.49(d,J=7.9Hz,1H), 6.86–6.58(m,3H), 5.48(dq,J=29.1,7.2Hz,1H), 4.96(t,J=5.6Hz,1H), 4.82 (dd,J=12.9,6.6Hz,1H), 4.10–3.92(m,2H), 3.79(dd,J=17.8,9.5Hz,4H), 3.58–3.49(m,2H), 3.38(s,3H) ), 3.15 (s, 1H), 1.96 (s, 1H), 1.65 (dd, J = 10.8, 7.4 Hz, 3H), 1.52 (d, J = 10.8 Hz, 1H).

Example 25 2-(6-(5-Chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxo Substituted pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl) -2-Hydroxyethyl)propionamide (Compound 25)

Compound 25 was prepared using a similar synthesis procedure in Example 9, using (3S,4R)-4-amino-3-hydroxytetrahydropyran hydrochloride as the starting material. MS: [M+H] ⁺ =602/604. ¹ H NMR(400MHz,DMSO-d ₆ )δ(ppm)8.75(dd,J=37.7,8.1Hz,1H),8.53-8.11(m,3H),7.60(dd,J=10.9,1.8Hz,1H ), 7.29 (d, J = 7.9Hz, 1H), 6.90-6.53 (m, 3H), 5.50 (dt, J = 21.7, 7.2 Hz, 1H), 4.95 (dd, J = 12.4, 5.5 Hz, 2H) ,4.83(dd,J=13.7,6.3Hz,1H),3.94-3.66(m,6H),3.66-3.42(m,3H),3.09(s,1H),1.98(d,J=15.9Hz,1H ), 1.78–1.54(m,3H), 1.57–1.38(m,1H).

Example 26 (R)-2-(6-(5-chloro-2-(((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl) -4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy Phenyl)-2-hydroxyethyl)propionamide (compound 26A) and (S)-2-(6-(5-chloro-2-(((3R,4R)-3-hydroxytetrahydro-2H- Pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-( (S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide (Compound 26B)

Compound 26A was prepared using a similar synthetic procedure to compound 9A in Example 9, using (3R, 4R)-4-amino-3-hydroxytetrahydropyran hydrochloride as the starting material. MS: [M+H] ⁺ =602/604. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.83 (d, J = 8.0 Hz, 1H), 8.33 (d, J = 10.7 Hz, 2H), 8.22 (s, 1H), 7.62 (d, J=1.8Hz,1H), 7.29(d,J=7.9Hz,1H), 6.78–6.60(m,3H), 5.52(q,J=7.3Hz,1H), 5.02–4.89(m,2H), 4.82 (dd, J = 13.7, 6.3 Hz, 1H), 3.83 (dd, J = 11.0, 5.1 Hz, 2H), 3.77 (s, 3H), 3.57 (dt, J = 7.2, 3.8 Hz, 2H), 3.53 –3.46(m,1H),3.09(s,1H),2.03–1.87(m,1H),1.64(d,J=7.4Hz,3H), 1.50(ddd,J=15.7,12.9,4.5Hz,1H ).

Compound 26B was prepared using a synthetic procedure similar to that of compound 9B in Example 9. MS: [M+H] ⁺ =602/604. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.72 (d, J = 8.1 Hz, 1H), 8.32 (d, J = 12.9 Hz, 2H), 8.20 (s, 1H), 7.59 (d, J=1.8Hz,1H), 7.29(d,J=8.0Hz,1H), 6.79–6.63(m,3H), 5.45(q,J=7.3Hz,1H), 5.02–4.91(m,2H), 4.81 (dd, J = 13.3, 6.8 Hz, 1H), 3.82 (dd, J = 11.0, 4.9 Hz, 2H), 3.76 (d, J = 6.8 Hz, 3H), 3.59 (dt, J = 11.7, 5.8 Hz , 2H), 3.54-3.46 (m, 2H), 3.08 (s, 2H), 1.96 (s, 1H), 1.66 (d, J=7.4 Hz, 3H), 1.55-1.42 (m, 1H).

Example 27 (R)-2-(7-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo [1,2-a]pyrazine-2(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide( Compound 27)

Compound 27 was prepared using a similar synthesis procedure in Example 11, using Intermediate 11.6 as the starting material. MS: [M+H] ⁺ =581/582. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 9.59 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 8.53 (s, 1H), 8.34 (d, J = 1.3 Hz, 1H), 7.70–7.49 (m, 2H), 7.39 (d, J = 1.7 Hz, 1H), 6.97 (d, J = 6.1 Hz, 1H), 6.71 (dd, J = 17.4, 6.6 Hz, 3H), 6.29(s,1H),5.53(q,J=7.2Hz,1H), 4.93(t,J=5.5Hz,1H), 4.83–4.73(m,1H),3.77(s,3H), 3.69(d , J = 13.1 Hz, 3H), 3.55 (dd, J = 14.4, 8.6 Hz, 2H), 1.50 (d, J = 7.3 Hz, 3H).

Example 28 2-(3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Amino)-1-oxoprop-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidine- 2-yl)amino)cyclobutyl)acetic acid (compound 28)

The synthesis method of compound 28 is similar to that of compound 9, and it is prepared with (3-amino-cyclobutyl)-acetic acid hydrochloride as the starting material. MS: [MH] ^- =612/614. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 11.98 (s, 1H), 8.77 (dd, J = 39.9, 8.0 Hz, 1H), 8.33 (s, 2H), 8.21 (d, J = 11.8 Hz, 1H), 7.60 (d, J = 7.1 Hz, 2H), 6.80-6.63 (m, 3H), 5.49 (ddd, J = 29.9, 14.5, 7.2 Hz, 1H), 4.97 (t, J = 5.3 Hz ,1H), 4.88–4.76(m,1H), 4.44(s,1H), 4.26(s,1H), 3.76(d,J=6.7Hz,3H),3.58(d,J=5.5Hz,2H) ,2.33(t,J=13.7Hz,2H),2.19(d,J=6.9Hz,1H),2.08(s,1H),1.69(s,1H),1.65(dd,J=10.7,7.4Hz, 3H).

Example 29 4-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)- 1-oxopropan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl )Amino)cyclohexane-1-carboxylic acid (Compound 29)

The synthetic method of compound 29 is similar to that of compound 9, prepared with 4-amino-cyclohexanecarboxylic acid hydrochloride as the starting material. MS: [MH] ^- =626/628. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 12.09 (s, 1H), 8.78 (dd, J = 38.3, 8.0 Hz, 1H), 8.38-8.23 (m, 2H), 8.21 (d, J = 11.3 Hz, 1H), 7.59 (dd, J = 11.1, 1.5 Hz, 1H), 7.31 (d, J = 6.3 Hz, 1H), 6.79-6.59 (m, 3H), 5.48 (dq, J = 29.6, 7.3Hz, 1H), 4.98 (t, J = 5.2 Hz, 1H), 4.86-4.72 (m, 1H), 3.85 (s, 1H), 3.76 (d, J = 7.1 Hz, 3H), 3.62-3.51 ( m, 2H), 2.45 (s, 1H), 1.97 (d, J=14.6 Hz, 2H), 1.72 (s, 2H), 1.65 (dd, J=10.5, 7.5 Hz, 7H).

Example 30 (1R,3S)-3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxy Ethyl)amino)-1-oxoprop-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl )Pyrimidin-2-yl)amino)cyclohexane-1-carboxylic acid (compound 30)

The synthesis method of compound 30 is similar to that of compound 9, and it is prepared with (1R,3S)-3-aminocyclohexane-1-carboxylic acid hydrochloride as the starting material. MS: [MH] ^- =626/628. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 11.98 (s, 1H), 8.80 (dd, J = 31.9, 7.5 Hz, 1H), 8.25 (t, J = 29.3 Hz, 3H), 7.59 ( d, J = 10.0Hz, 1H), 7.34 (d, J = 7.8Hz, 1H), 6.94-6.52 (m, 3H), 5.48 (dq, J = 29.8, 7.4 Hz, 1H), 5.01 (s, 1H) ), 4.87–4.70(m,1H), 3.76(d,J=7.2Hz,3H), 3.65–3.50(m,2H), 2.34(s,1H), 2.14(d,J=12.0Hz,1H) , 1.83 (dd, J = 33.0, 12.6 Hz, 2H), 1.64 (dd, J = 9.6, 7.6 Hz, 2H), 1.53-1.04 (m, 4H).

Example 31 (1R,3S)-3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxy Ethyl)amino)-1-oxoprop-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl )Pyrimidin-2-yl)amino)cyclopentane-1-carboxylic acid (compound 31)

The synthesis method of compound 31 is similar to that of compound 9, and it is prepared with (1R,3S)-3-aminocyclopentane-1-carboxylic acid hydrochloride as the starting material. MS: [MH] ^- =612/614. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 11.97 (s, 1H) 8.81 (dd, J = 35.0, 8.0 Hz, 1H), 8.53-8.04 (m, 3H), 7.60 (d, J = 10.6Hz, 1H), 7.51 (s, 1H), 5.49 (dd, J = 30.2, 7.1 Hz, 1H), 5.01 (s, 1H), 4.91-4.58 (m, 1H), 4.23 (s, 2H), 3.76(d,J=7.3Hz,3H), 3.67–3.50(m,2H), 2.73(d,J=37.0Hz,1H), 2.29(d,J=35.8Hz,1H), 1.93–1.77(m , 2H), 1.66 (dd, J = 20.6, 12.5 Hz, 3H).

Example 32 3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)- 1-oxopropan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl )Amino)cyclobutane-1-carboxylic acid (Compound 32)

The synthetic method of compound 32 is similar to that of compound 9, and it is prepared with 3-amino-cyclobutane carboxylic acid hydrochloride as the starting material. MS: [MH] ^- =598/600. ¹ H NMR (400MHz, DMSO-d ₆ ) δ (ppm) 8.79 (dd, J = 39.2, 8.0 Hz, 1H), 8.41-8.25 (m, 2H), 8.25-8.15 (m, 1H), 7.75 (dd ,J=22.0,7.1Hz,1H), 7.66–7.52(m,1H), 6.78–6.60(m,3H), 5.57–5.40(m,1H), 4.98(t,J=5.1Hz,1H), 4.88–4.73(m,1H),4.59–4.42(m,1H), 4.34(s,1H), 3.76(d,J=6.9Hz,3H),3.58(d,J=5.3Hz,2H),2.97 (s, 1H), 2.81 (d, J = 7.8 Hz, 1H), 2.31 (dd, J = 21.6, 5.6 Hz, 1H), 2.15 (dd, J = 18.7, 9.1 Hz, 1H), 1.65 (dd, J=10.6, 7.5 Hz, 3H).

Example 33 (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2 ,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide (Compound 33)

Compound 33 was prepared using a similar synthetic procedure to compound 1 in Example 1, with (2S)-2-amino-2-(3-methylphenyl)ethan-1-ol as the starting material. MS: [M+H] ⁺ =552/554. ¹ H NMR(400MHz,DMSO)δ8.82(d,J=8.0Hz,1H), 8.48-8.10(m,2H), 7.61(d,J=1.6Hz,1H), 7.41(t,J=9.9 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.08 (dd, J = 15.5, 8.1 Hz, 2H), 5.53 (q, J = 7.3 Hz, 1H), 4.91 (dd, J = 28.8 ,23.4Hz,1H),4.79(dd,J=13.4,7.0Hz,1H),4.02(dt,J=19.2,9.6Hz,1H),3.88(d,J=11.2Hz,2H),3.64–3.45 (m, 2H), 3.43 (s, 2H), 2.37-2.15 (m, 3H), 1.85 (s, 2H), 1.66-1.48 (m, 3H), 1.60-1.42 (m, 2H).

Example 34 With reference to the preparation method of Example 11 or Example 27, compounds 34-40 were synthesized using different intermediates or their salt forms, as shown in Table 1.

Table 1

Example 35 ERK2 Enzyme Inhibition Test

ERK2 was expressed in the Escherichia coli system, which was purchased from Carna Biosciences, Inc. (Japan, CK). ULight-MBP Peptide, Europium-anti-phospho-Myelin Basic Protein (Thr232) antibody and LANCE Detection Buffer were purchased from PerkinElmer (Waltham, MA). High-purity ATP, DTT, EDTA, EGTA, Tween-20, DMSO and Tris buffer were purchased from Sigma.

The assay buffer used in the experiment consisted of 50mM Tris (pH 7.5), 1mM EGTA, 10mM MgCl ₂ , 0.01% Tween-20 and 2mM DTT. 4% DMSO compound, ERK2 enzyme and ULight-MBP Peptide/ATP mixed solution are prepared using assay buffer. After preparation, 2.5 μL 4% DMSO compound, 5 μL ERK2 and 2.5 μL ULight-MBP Peptide/ATP mixed solution are prepared respectively Add it to the Opti Plate-384 White well plate, cover with a film, and incubate at room temperature for 1.5 hours at 800 revolutions for 1 min. The final concentrations of ERK2, ULight-MBP Peptide, ATP and DMSO are 2nM, 30nM, 5μM and 1%, respectively. After 1.5h, 5μL of 40mM EDTA (prepared in detection buffer) was added to the reaction mixture to terminate the reaction, and the termination time was 5min. Then add 5μL of detection antibody (final concentration 2nM, prepared in detection buffer), and incubate at room temperature for 1h. Read the plate on the TECAN (Switzerland) SPARK multifunctional microplate reader. The excitation light wavelength is 320 nm and the emission light wavelength is 665 nm. A S-shaped dose response model (variable slope, four parameters) was used in Prism 7 (LaJolla, CA) to determine the concentration (IC50 value) of the compound that inhibited cell survival by 50%.

The results of the ERK2 enzyme inhibition test of the representative compounds described herein are shown in Table 2.

Table 2

Compound IC50(nM) Compound IC50(nM) 1 0.93 16 4 2 3.57 17A 3 3 N/A 17B 140 4 N/A 18A 5 5A 2.52 18B 320 5B N/A 19A 8 6A N/A 19B 1360 6B N/A 20A 1.49 7A N/A 20B 81.33 7B N/A twenty one 6.14 8A 4.91 twenty two 9.19 8B N/A 23A 5.69 9A 5.43 23B 303 9B N/A twenty four 4.24 10A 1.19 25 6.33 10B N/A 26A 6.67 11A 0.95 26B 116.4 11B N/A 27 1.99 12A 2.25 28 42.46 12B 602 29 568.8 13A 35.8 30 91.35 13B 2670 31 24.13 14A 27.5 32 83.13 14B 2518 33 0.86 15A 10 Ulixertinib 0.54 15B 1880 ASTX-029 0.55

According to the test results of Table 2, most of these compounds have obvious ERK2 inhibitory activity, and the ERK inhibitory activity of some of them has similar results with the existing positive reference, especially compound 1, compound 10A, compound 11, compound 12A and compound 33.

Example 36 Non-B-RAF mutant WT cell proliferation inhibition test

Materials and cell lines

购自Promega Corporation(Madison,WI,USA)。 NCI-H508, SW-48 and MKN-45 cells were purchased from the Chinese Academy of Sciences Cell Bank (Shanghai). DMEM medium, RPMI1640 medium, penicillin-streptomycin double antibody and 0.5% pancreatin (10X) were purchased from ThermoFisher (Waltham, MA, USA). Certified fetal bovine serum (FBS) was purchased from Biological Industries (Israel). Corning 96 and 384-well cell culture plates were purchased from CORNING (USA). Cell-Titer

Purchased from Promega Corporation (Madison, WI, USA).

In order to evaluate the ability of synthetic compounds to inhibit the proliferation of gastric cancer MKN-45 cells, human colon cancer NCI-H508 and SW-48 cells, cells with exponential growth of MKN-45 and NCI-H508 were inoculated with 10% bovine serum and 1% penicillin. -Streptomycin RPMI1640 medium, SW-48 exponentially growing cells were inoculated in DMEM medium containing 10% bovine serum and 1% penicillin-streptomycin double antibody, with a density of 125,000, 100,000 and 300,000 cells, respectively /mL, 384-well plate, 20μL per well, and placed in a 37°C, 5% CO ₂ incubator overnight. The compound was diluted in DMSO to a 12-point, 3-fold serial dilution, starting from 6mM. Add 1 μL of DMSO solution of the compound stock plate to 99 μL of cell culture medium (the final maximum concentration of the compound in the assay is 30 μM, and the final concentration of DMSO is 0.5%). Add 20 μL of the compound solution in the culture medium to each well of the MKN-45, NCI-H508 and SW-48 cell plates. After adding the compound solution, the 384-well plate was placed in a 37°C, 5% CO ₂ incubator and incubated for 4 days. Promega (Madison, WI, USA)'s CellTiter-Glo detection kit was used to determine cell viability by quantifying the ATP present in cell culture. After 20 minutes of incubation, the SPARK multi-function microplate reader from TECAN was used for reading under the chemiluminescence program. A S-shaped dose response model (variable slope, four parameters) was used in Prism 7 (LaJolla, CA) to determine the concentration (IC50 value) of the compound that inhibited cell survival by 50%.

The results of the non-B-RAF mutant cell proliferation inhibition test of the representative compounds described herein are shown in Table 3.

table 3

Analyzed from the results in Table 3, the compound of the present application has much lower proliferation inhibitory activity against non-B-RAF mutant WT cells such as MKN-45 (WT), NCI-H508 (WT), SW-48 (WT), etc., than ASTX-029. The selectivity of BRAF-mutated sensitive cells was significantly higher than the two listed positive compounds.

Example 37 Phosphorylation ERK1/2 (Thr202/Tyr204) test

For p-ERK cell experiment, use advance phospho-ERK1/2 Kit (Cisbio). Refer to the manufacturer’s instructions. The steps are as follows: A375 cells (5000cells/well) and Colo205 cells (50000cells/well) are respectively seeded into 96-well culture plates In the medium, 37℃, 5% CO ₂ incubator overnight (A375), Colo205 cells do not need to stay overnight. Then add the inhibitor of ERK1/2, and _{incubate in a 37℃, 5% CO 2} incubator for 30 minutes, the concentration of ERK inhibitor is 30,10,3.3,1.1,0.37,0.12,0.04,0.01,0.005,0.002 , 0.0005 and 0.0002μM. The incubation was terminated by adding supplemented lysis buffer and shaking at room temperature for at least 30 minutes. After the cells are completely lysed, gently pipette up and down to mix. Aspirate 16μL of cell lysate from the 96-well plate to the OptiPlate-384 White well plate, and then add 4μl of an equal volume of mixed detection antibody (prepared in detection buffer), cover the membrane, Incubate at room temperature for 4h. Read the plate on the SPARK multifunctional microtiter plate of TECAN (Switzerland), the excitation light wavelength is 320nm, and the emission light wavelength is 665nm. A S-shaped dose response model (variable slope, four parameters) was used in Prism 7 (LaJolla, CA) to determine the concentration (IC50 value) of the compound that inhibited cell survival by 50%.

The results of the phosphorylated ERK1/2 (Thr202/Tyr204) test of the representative compounds described herein are shown in Table 4.

Table 4

The experimental results in Table 4 show that the compound of the present application can simultaneously inhibit the phosphorylation of ERK1/2 downstream and the phosphorylation of ERK1/2 itself.

Example 38 Pharmacokinetic Experiment

Male CD-1 mice (purchased from JH Laboratory Animal Co. LTD; 19-27g; 6-8 weeks; n=18, 9 mice per route of administration, 3 animals at each time point) were tested with a single compound Under the dosage condition, they were administered by tail vein injection (2mg/kg) and oral feeding (10mg/kg). The compound solutions used were all containing 5% N,N-dimethyl sulfoxide (DMSO) and 10% Polyethylene glycol 15 hydroxystearate (Solutol HS15) is formulated in physiological saline containing 20% hydroxypropyl-β-cyclodextrin (HP-β-CD). The animals in the oral administration group fasted overnight on the day before the administration and took food 4 hours after the administration. Animals in the intravenous administration group have free access to food and drinking water after administration. The research complies with the guidelines and standards of the Association for the Evaluation and Accreditation of Laboratory Animal Management (AAALAC) and the National Institutes of Health. At the designated sampling time point, after using isoflurane anesthetized the animal, through facial vein or cardiac puncture, under isoflurane inhalation anesthesia using staggered bleeding to collect about 110μL of blood sample into the EDTA-2K tube for storage. The collected blood samples were kept in wet ice and centrifuged within 15 minutes after sampling to obtain plasma (2000g, 4°C, 5min). The plasma samples are stored in freezing conditions at approximately -70°C until analysis. Before analyzing the collected plasma samples, add an aliquot of 30 μL of the undiluted plasma sample to 200 μL IS (acetonitrile solution containing 300 ng/mL diclofenac or 20 ng/mL glipizide). The mixture was vortexed at 750 rpm for 10 min and centrifuged at 6000 rpm for 10 min. Take a 3 μL aliquot of the supernatant and use UPLC-MS/MS-010 (API-4000) for quantitative analysis of compound concentration. A standard calibration curve was constructed by analyzing a series of control plasma aliquots containing diclofenac (300ng/mL) or glipizide (20ng/mL) as internal controls of 3.0-3,000ng/mL test compounds. For 10-fold diluted plasma samples, add an aliquot of 3 μL of blood sample to 27 μL of blank diluted plasma with a dilution factor of 10. The subsequent operation is the same as the above-mentioned undiluted plasma sample.

See Table 5 and Table 6 for the PK results of the representative compounds described herein.

table 5

*Reference value

Table 6

The experimental results in Table 5 and Table 6 show that the PK data of these compounds are mostly better than the positive drug Ulixertinib and the positive drug ASTX-029, especially the compounds 1,10A, 11, and 27 are more obvious, and their bioavailability is similar to the positive drug. But the clearance rate in vivo is lower than Ulixertinib, and much lower than ASTX-029. Cmax and AUC were significantly better than the positive drug Ulixertinib and the positive drug ASTX-029. Better pharmacokinetic properties, combined with excellent enzyme activity inhibition activity, and higher selectivity of sensitive cells, will show a therapeutic window far better than positive compounds in vivo, and better clinical efficacy and safety Sex.

Claims (23)

Compound of formula (I):

Or its isomer or pharmaceutically acceptable salt; Wherein, X and Y are independently selected from C or N; R ^{1 is} selected from C _1-6 alkyl, 3- to 9-membered cycloalkyl, 3- to 9-membered heterocycloalkyl containing 1-3 N or O, aryl or containing 1-3 N or O Wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted with one or more R ⁶ , wherein R ^{6 is} selected from C _{1 -6} alkyl, halogen, hydroxy, carbonyl, amino, cyano, alkoxy, -(CH ₂ ) _n COOH or -(CO)(CH ₂ ) _n CH ₃ ; R ^{2 is} selected from hydrogen, halogen, alkoxy or C _1-6 alkyl optionally substituted with one or more fluorine atoms; R ^{3 is} selected from ^{an aryl group optionally substituted with 0-3 R 7} or a 5- to 6-membered heteroaryl group, wherein R ^{7 is} selected from halogen, alkoxy or optionally substituted with one or more fluorine atoms C _1-6 alkyl; R ^{4 is} selected from -(CH ₂ ) _n OH or -COOH; R ^{5 is} selected from C _1-6 alkyl; and Each n is independently an integer between 0-3. The compound of claim 1, wherein formula (I) is formula (Ia):

Wherein R ¹ , R ² , R ³ , R ⁴ , X and Y have the meanings defined in claim 1. The compound according to claim 2, wherein: R ^{2 is} _{selected from hydrogen, halogen or C 1-6} alkyl optionally substituted with one or more fluorine atoms; R ^{3 is} selected from optionally 0-3 R ⁷ substituted aryl, wherein R ^{7 is} _{selected from halogen, alkoxy or C 1-6} alkyl optionally substituted with one or more fluorine atoms; R ⁴ is -(CH ₂ ) _n OH; and each Each n is independently an integer between 0-3. The compound of claim 1, wherein the formula (I) is the formula (I b):

Wherein R ^{2 is} selected from hydrogen, chlorine or trifluoromethyl; R ^{7 is} selected from halogen, methyl, methoxy or trifluoromethyl; and R ¹ , X and Y have the meanings defined in claim 1. The compound according to claim 4, wherein the formula (I b) is the formula (I b-1):

Wherein R ¹ , R ² and R ⁷ have the meaning defined in claim 4. The compound according to claim 4, wherein the formula (I b) is the formula (I b-2):

Wherein R ¹ , R ² and R ⁷ have the meaning defined in claim 4. The compound according to claim 4, wherein the formula (I b) is the formula (I b-3):

Wherein R ¹ , R ² and R ⁷ have the meaning defined in claim 4. The compound of claim 4, wherein the formula (I b) is the formula (I b-4):

Wherein R ¹ , R ² and R ⁷ have the meaning defined in claim 4. The compound of claim 1, which is selected from: (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyridin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide; (R)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)-2-(4-oxo-6-(2-((tetrahydro-2H-pyran-4 -Yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)propionamide; (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(3-(trifluoromethyl)phenyl)ethyl)propionamide ； (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3,5-dimethylphenyl)-2-hydroxyethyl)propionamide; (S)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3,5-dimethylphenyl)-2-hydroxyethyl)propionamide; (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-phenylethyl)propionamide; (S)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-phenylethyl)propionamide; (R)-2-(6-(5-Chloro-2-((4,4-difluorocyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][ 1,2,4]Triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide; (S)-2-(6-(5-Chloro-2-((4,4-difluorocyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][ 1,2,4]Triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide; (2R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)propionamide; (2S)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)propionamide; (R)-2-(6-(5-Chloro-2-(isopropylamino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]Three Azin-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; (S)-2-(6-(5-Chloro-2-(isopropylamino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]Three Azin-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; (R)-2-(6-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2, 1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl ) Propionamide; (S)-2-(6-(5-Chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2, 1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl ) Propionamide; (R)-2-(7-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1,2- a] pyrazine-2-(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; (S)-2-(7-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1,2- a] pyrazine-2-(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; (2R)-2-(6-(2-((8-oxabicyclo[3.2.1]oct-3-yl)amino)-5-chloropyrimidin-4-yl)-4-oxopyrrolo[ 2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxy Ethyl) propionamide; (2S)-2-(6-(2-((8-oxabicyclo[3.2.1]oct-3-yl)amino)-5-chloropyrimidin-4-yl)-4-oxopyrrolo[ 2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxy Ethyl) propionamide; (R)-2-(6-(5-Chloro-2-(((R)-3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy (Phenyl)-2-hydroxyethyl)propionamide; (S)-2-(6-(5-Chloro-2-(((R)-3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy (Phenyl)-2-hydroxyethyl)propionamide; (R)-2-(6-(5-chloro-2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f] [1,2,4]Triazine-3(4H)-yl)-N-((S)-1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)propionamide; (S)-2-(6-(5-chloro-2-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f] [1,2,4]Triazine-3(4H)-yl)-N-((S)-1-(3-chloro-5-fluorophenyl)-2-hydroxyethyl)propionamide; (R)-2-(6-(5-Chloro-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy (Phenyl)-2-hydroxyethyl)propionamide; (S)-2-(6-(5-Chloro-2-(((R)-2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)- 4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxy (Phenyl)-2-hydroxyethyl)propionamide; N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(4-oxo-6-(2-((tetrahydro-2H- Pyran-4-yl)amino)pyrimidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)propionamide; (R)-2-(6-(5-Chloro-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4 -Oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxybenzene Yl)-2-hydroxyethyl)propionamide; (S)-2-(6-(5-Chloro-2-(((3S,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4 -Oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxybenzene Yl)-2-hydroxyethyl)propionamide; (R)-2-(6-(5-Chloro-2-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1 -f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Propionamide (S)-2-(6-(5-Chloro-2-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1 -f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Propionamide (R)-2-(6-(5-Chloro-2-((3,3-difluorocyclic)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1 ,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; (S)-2-(6-(5-Chloro-2-((3,3-difluorocyclic)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1 ,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; (R)-N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(6-(5-methyl-2-((四Hydrogen-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl) Propionamide (S)-N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(6-(5-methyl-2-((四Hydrogen-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl) Propionamide 2-(6-(5-Chloro-2-((1-methyl-2-oxopiperidin-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide 2-(6-(2-((1-Acetylpiperidin-4-yl)amino)-5-chloropyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1, 2,4]Triazine-3-(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; (R)-2-(6-(5-Chloro-2-(((1r,4R)-4-methoxycyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2, 1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl ) Propionamide; (S)-2-(6-(5-Chloro-2-(((1r,4S)-4-methoxycyclohexyl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2, 1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl ) Propionamide; 2-(6-(5-chloro-2-(((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxo Pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)- 2-hydroxyethyl) propionamide; 2-(6-(5-Chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo [2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2- Hydroxyethyl) propionamide; (R)-2-(6-(5-Chloro-2-(((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4- Oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl) )-2-hydroxyethyl)propionamide; (S)-2-(6-(5-Chloro-2-(((3R,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4- Oxopyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl) )-2-hydroxyethyl)propionamide; (R)-2-(7-(5-chloro-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1, 2-a]pyrazine-2(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; 2-(3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)- 1-oxopropan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl )Amino)cyclobutyl)acetic acid; 4-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)-1-oxy Propan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl)amino) Cyclohexane-1-carboxylic acid; (1R,3S)-3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Amino)-1-oxoprop-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidine- 2-yl)amino)cyclohexane-1-carboxylic acid; (1R,3S)-3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Amino)-1-oxoprop-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidine- 2-yl)amino)cyclopentane-1-carboxylic acid; 3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)-1-oxy Propan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl)amino) Cyclobutane-1-carboxylic acid; (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide; (R)-2-(7-(5-Chloro-2-(isopropylamino)pyrimidin-4-yl)-1-oxopyrrolo[1,2-a]pyrazine-2(1H)- Yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; (2R)-2-(7-(5-chloro-2-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxo Pyrrolo[1,2-a]pyrazine-2(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide (2R)-2-(7-(5-chloro-2-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxo Pyrrolo[1,2-a]pyrazine-2(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide (R)-2-(7-(5-chloro-2-(((3R,4R)-3-methyltetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1 -Oxopyrrolo[1,2-a]pyrazine-2(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl Base) propionamide; (R)-N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(1-oxo-7-(2-((四Hydrogen-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyrrolo[1,2-a]pyrazine-2(1H)-yl)propionamide; (R)-2-(7-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1,2- a] pyrazine-2-(1H)-yl)-N-((S)-2-hydroxy-1-(m-tolyl)ethyl)propionamide; or (R)-2-(7-(5-chloro-2-(((1S,3R)-3-hydroxycyclopentyl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1,2 -a] Pyrazin-2-(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide. The compound of claim 9 which is: N-((S)-1-(3-Fluoro-5-methoxyphenyl)-2-hydroxyethyl)-2-(4-oxo-6-(2-((tetrahydro-2H- Pyran-4-yl)amino)pyrimidin-4-yl)pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)propionamide; 2-(6-(5-Chloro-2-((1-methyl-2-oxopiperidin-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide 2-(6-(2-((1-Acetylpiperidin-4-yl)amino)-5-chloropyrimidin-4-yl)-4-oxopyrrolo[2,1-f][1, 2,4]Triazine-3-(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide; 2-(6-(5-chloro-2-(((3S,4R)-3-methoxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxo Pyrrolo[2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)- 2-hydroxyethyl) propionamide; 2-(6-(5-Chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo [2,1-f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2- Hydroxyethyl) propionamide; 2-(3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)- 1-oxopropan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl )Amino)cyclobutyl)acetic acid; 4-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)-1-oxy Propan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl)amino) Cyclohexane-1-carboxylic acid; (1R,3S)-3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Amino)-1-oxoprop-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidine- 2-yl)amino)cyclohexane-1-carboxylic acid; (1R,3S)-3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl) Amino)-1-oxoprop-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidine- 2-yl)amino)cyclopentane-1-carboxylic acid; or 3-((5-chloro-4-(3-(1-(((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)amino)-1-oxy Propan-2-yl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-6-yl)pyrimidin-2-yl)amino) Cyclobutane-1-carboxylic acid. The compound of claim 9 which is: (R)-2-(6-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4-oxopyrrolo[2,1- f][1,2,4]triazine-3(4H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propane Amide. The compound of claim 9 which is: (R)-2-(7-(5-Chloro-2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-1-oxopyrrolo[1,2- a] Pyrazin-2-(1H)-yl)-N-((S)-1-(3-fluoro-5-methoxyphenyl)-2-hydroxyethyl)propionamide. Use of the compound according to any one of claims 1-12 for the preparation of drugs for preventing or treating ERK1/2-mediated diseases. The use according to claim 13, wherein the ERK1/2-mediated disease is cancer. The use according to claim 14, wherein the cancer is non-small cell lung cancer, pancreatic cancer, colon cancer, gastric cancer, lymphoma or melanoma. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1-12 and a pharmaceutically acceptable carrier or excipient. Compound of formula (II):

Wherein, R ^{8 is} selected from halogen, boronic acid group or pinacol borane; R ^{9 is} selected from C _1-6 alkyl; and Y is selected from C or N. The compound of claim 17, wherein the formula (II) is the formula (IIa):

Wherein R ^{8 is} selected from halogen, boronic acid group or pinacol borane; R ^{9 is} selected from C _1-6 alkyl; and Y is selected from C or N. The compound according to claim 17 or 18, wherein R ^{8 is} selected from fluorine, chlorine, bromine, iodine, boronic acid or pinacol borane, and R ^{9 is} selected from methyl, ethyl, isopropyl or n-butyl And Y is selected from C or N. Compound of formula (Ⅲ):

Wherein, R ^{11 is} selected from halogen or -NHR ¹ ; R ^{10 is} selected from hydrogen or C _1-6 alkyl; and X, Y, R ¹ and R ² have the meanings defined in claim 1. The compound according to claim 20, wherein the formula (III) is the formula (IIIa):

Wherein R ^{11 is} selected from halogen or -NHR ¹ ; R ^{10 is} selected from hydrogen or C _1-6 alkyl; and X, Y, R ¹ and R ² have the meanings defined in claim 1. The compound according to claim 20 or 21, wherein R ^{11 is} selected from fluorine, chlorine, bromine, iodine or -NHR ¹ ; R ^{10 is} selected from hydrogen, methyl, ethyl, isopropyl or n-butyl; and X , Y, R ¹ and R ² have the meanings defined in claim 1. The use of a compound of any one of claims 17 to 22 for preparing the compound of claim 1.